Amino-5,5-diphenylimidazolone derivatives for the inhibition of beta-secretase

ABSTRACT

The present invention provides a compound of formula I and the use thereof for the therapeutic treatment, prevention or amelioration of a disease or disorder characterized by elevated β-amyloid deposits or β-amyloid levels in a patient.

This application claims the benefit under 35 U.S.C. §119(e) toco-pending U.S. provisional application No. 60/580286, filed Jun. 16,2004, which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD), a progressive degenerative disease of thebrain primarily associated with aging, is a serious healthcare problem.Clinically, AD is characterized by the of loss of memory, cognition,reasoning, judgment, and orientation. Also affected, as the diseaseprogresses, are motor, sensory, and linguistic abilities until globalimpairment of multiple cognitive functions occurs. These cognitivelosses take place gradually, but typically lead to severe impairment andeventual death in 4-12 years. Patients with AD display characteristicβ-amyloid deposits in the brain and in cerebral blood vessels (β-amyloidangiopathy) as well as neurofibrillary tangles. Amyloidogenic plaquesand vascular amyloid angiopathy also characterize the brains of patientswith Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage withAmyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerativedisorders. Neurofibrillary tangles also occur in other dementia-inducingdisorders.

The family of proteins known as β-amyloid are thought to be causal forthe pathology and subsequent cognitive decline in Alzheimer's disease.Proteolytic processing of the amyloid precursor protein (APP) generatesamyloid β (A-beta) peptide; specifically, A-beta is produced by thecleavage of APP at the N-terminus by β-secretase and at the C-terminusby one or more γ-secretases. Aspartyl protease enzyme, or β-secretaseenzyme (BACE), activity is correlated directly to the generation ofA-beta peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540).Increasingly, studies indicate that the inhibition of the β-secretaseenzyme, inhibits the production of A-beta peptide. The inhibition ofβ-secretase and consequent lowering of A-beta peptide may lead to thereduction of β-amyloid deposits in the brain and β-amyloid levels in thecerebral blood vessels and to an effective treatment of a disease ordisorder caused thereby.

Therefore, it is an object of this invention to provide compounds whichare inhibitors of β-secretase and are useful as therapeutic agents inthe treatment, prevention or amelioration of a disease or disordercharacterized by elevated β-amyloid deposits or β-amyloid levels in apatient.

It is another object of this invention to provide therapeutic methodsand pharmaceutical compositions useful for the treatment, prevention oramelioration of a disease or disorder characterized by elevatedβ-amyloid deposits or β-amyloid levels in a patient.

It is a feature of this invention that the compounds provided may alsobe useful to further study and elucidate the β-secretase enzyme.

These and other objects and features of the invention will become moreapparent by the detailed description set forth hereinbelow.

SUMMARY OF THE INVENTION

The present invention provides an amino-5,5-diphenylimidazolone compoundof formula I

wherein W is CO, CS or CH₂;

-   -   X is N, NO or CR₁₀;    -   Y is N, NO or CR₁₁;    -   Z is N, NO or CR₁₉ with the proviso that no more than two of X,        Y or Z may be N or NO;    -   R₁ and R₂ are each independently H, COR₂₀, CO₂R₂₁ or an        optionally substituted C₁-C₄alkyl group;    -   R₃ is H, OR₁₂ or a C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₈cycloalkyl or aryl(C₁-C₆)alkyl group each        optionally substituted;    -   R₄ and R₅ are each independently H, halogen, NO₂, CN, OR₁₃,        NR₁₄R₁₅ or a C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl or C₃-C₈cycloalkyl group each optionally        substituted or when attached to adjacent carbon atoms R₄ and R₅        may be taken together with the atoms to which they are attached        to form an optionally substituted 5- to 7-membered ring        optionally containing one or two heteroatoms selected from O, N        or S;    -   R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₉ are each independently H,        halogen, NO₂, CN, OR₁₆, NR₁₇R₁₈ or a C₁-C₆alkyl, C₁-C₆haloalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈cycloalkyl group each        optionally substituted;    -   n is 0 or 1;    -   is a single bond when n is 0 or a double bond when n is 1;    -   R₁₂, R₁₃, R₁₆, R₂₀ and R₂₁ are each independently H or a        C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        C₃-C₈cycloalkyl or aryl group each optionally substituted; and    -   R₁₄, R₁₅, R₁₇ and R₁₈ are each independently H or C₁-C₄alkyl; or        a tautomer thereof, a stereoisomer thereof or a pharmaceutically        acceptable salt thereof.

The present invention also provides therapeutic methods andpharmaceutical compositions useful for the treatment, prevention oramelioration of a disease or disorder characterized by increasedβ-amyloid deposits or increased β-amyloid levels in a patient.

DETAILED DESCRIPTION OF THE INVENTION

Alzheimer's disease (AD) is a major degenerative disease of the brainwhich presents clinically by progressive loss of memory, cognition,reasoning, judgement and emotional stability and gradually leads toprofound mental deteoriation and death. The exact cause of AD isunknown, but increasing evidence indicates that amyloid beta peptide(A-beta) plays a central role in the pathogenesis of the disease. (D. B.Schenk; R. E. Rydel et al, Journal of Medicinal Chemistry, 1995, 21,4141and D. J. Selkoe, Physiology Review, 2001, 81, 741). Patients with ADexhibit characteristic neuropathological markers such as neuriticplaques (and in β-amyloid angiopathy, deposits in cerebral bloodvessels) as well as neurofibrillary tangles detected in the brain atautopsy. A-beta is a major component of neuritic plaques in AD brains.In addition, β-amyloid deposits and vascular β-amyloid angiopathy alsocharacterize individuals with Downs Syndrome, Hereditary CerebralHemmorhage with Amyloidosis of the Dutch type and otherneurodegenreative and dementia-inducing disorders. Over expression ofthe amyloid precursor protein (APP), altered cleavage of APP to A-betaor a decrease in the clearance of A-beta from a patient's brain mayincrease the levels of soluble or fibrullar forms of A-beta in thebrain. The β-site APP cleaving enzyme, BACE1, also called memapsin-2 orAsp-2, was identified in 1999 (R. Vassar, B. D. Bennett, et al, Nature,1999, 402, 537). BACE1 is a membrane-bound aspartic protease with allthe known functional properties and characteristics of β-secretase.Parallel to BACE1, a second homologous aspartyl protease named BACE2 wasfound to have β-secretase activity in vitro. Low molecular weight,non-peptide, non-substrate-related inhibitors of BACE1 or β-secretaseare earnestly sought both as an aid in the study of the β-secretaseenzyme and as potential therapeutic agents.

Surprisingly, it has now been found that amino-5,5-diphenylimidazolonecompounds of formula I demonstrate inhibition of β-secretase and theselective inhibition of BACE1. Advantageously, said imidazolonecompounds may be used as effective therapeutic agents for the treatment,prevention or amelioration of a disease or disorder characterized byelevated β-amyloid deposits or β-amyloid levels in a patient.Accordingly, the present invention provides anamino-5,5-diphenylimidazolone compound of formula I

wherein W is CO, CS or CH₂;

-   -   X is N, NO or CR₁₀;    -   Y is N, NO or CR₁₁;    -   Z is N, NO or CR₁₉ with the proviso that no more than two of X,        Y or Z may be N or NO;    -   R₁ and R₂ are each independently H, COR₂₀, CO₂R₂₁ or an        optionally substituted C₁-C₄alkyl group;    -   R₃ is H, OR₁₂ or a C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₈cycloalkyl or aryl(C₁-C₆)alkyl group each        optionally substituted;    -   R₄ and R₅ are each independently H, halogen, NO₂, CN, OR₁₃,        NR₁₄R₁₅ or a C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl or C₃-C₈cycloalkyl group each optionally        substituted or when attached to adjacent carbon atoms R₄ and R₅        may be taken together with the atoms to which they are attached        to form an optionally substituted 5- to 7-membered ring        optionally containing one or two heteroatoms selected from O, N        or S;    -   R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₉ are each independently H,        halogen, NO₂, CN, OR₁₆, NR₁₇R₁₈ or a C₁-C₆alkyl, C₁-C₆haloalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈cycloalkyl group each        optionally substituted;    -   n is 0 or 1;    -   is a single bond when n is 0 or a double bond when n is 1;    -   R₁₂, R₁₃, R₁₆, R₂₀ and R₂₁ are each independently H or a        C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        C₃-C₈cycloalkyl or aryl group each optionally substituted; and    -   R₁₄, R₁₅, R₁₇ and R₁₈ are each independently H or C₁-C₄alkyl; or        a tautomer thereof, a stereoisomer thereof or a pharmaceutically        acceptable salt thereof.

As used in the specification and claims, the term halogen designates F,Cl, Br or I and the term cycloheteroalkyl designates a five- toseven-membered cycloalkyl ring system containing 1 or 2 heteroatoms,which may be the same or different, selected from N, O or S andoptionally containing one double bond. Exemplary of the cycloheteroalkylring systems included in the term as designated herein are the followingrings wherein X₁ is NR, O or S; and R is H or an optional substituent asdescribed hereinbelow:

Similarly, as used in the specification and claims, the term heteroaryldesignates a five- to ten-membered aromatic ring system containing 1, 2or 3 heteroatoms, which may be the same or different, selected from N, Oor S. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl,thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl,indolyl, benzothienyl, benzofuranyl, benzisoxazolyl or the like. Theterm aryl designates a carbocyclic aromatic ring system such as phenyl,naphthyl, anthracenyl or the like. The term aryl(C₁-C₄)alkyl designatesan aryl group as defined hereinabove attached to a C₁-C₄alkyl groupwhich may be straight or branched. Said aryl(C₁-C₄)alkyl groups includebenzyl, phenethyl, napthtylmethyl, or the like. The term haloalkyl asused herein designates a C_(n)H_(2n+1) group having from one to 2n+1halogen atoms which may be the same or different and the term haloalkoxyas used herein designates an OC_(n)H_(2n+1) group having from one to2n+1 halogen atoms which may be the same or different. Preferably theterm haloalkyl designates CF₃ and the term haloalkoxy designates OCF₃.

In the specification and claims, when the terms C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl, aryl,aryl(C₁-C₄)alkyl or heteroaryl are designated as being optionallysubstituted, the substituent groups which are optionally present may beone or more of those customarily employed in the development ofpharmaceutical compounds or the modification of such compounds toinfluence their structure/activity, persistence, absorption, stabilityor other beneficial property. Specific examples of such substituentsinclude halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl,alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino,formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl,alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl,benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atomsor lower alkyl or lower alkoxy groups. Typically, 0-3 substituents maybe present. When any of the foregoing substituents represents orcontains an alkyl substituent group, this may be linear or branched andmay contain up to 12, preferably up to 6, more preferably up to 4 carbonatoms.

Pharmaceutically acceptable salts may be any acid addition salt formedby a compound of formula I and a pharmaceutically acceptable acid suchas phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic,malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic,p-toluene sulfonic, methane sulfonic acid or the like.

Compounds of the invention include amides, esters, carbamates or otherconventional prodrug forms, which in general, are functional derivativesof the compounds of the invention and which are readily converted to theinventive active moiety in vivo. Correspondingly, the method of theinvention embraces the treatment of the various conditions describedhereinabove with a compound of formula I or with a compound which is notspecifically disclosed but which, upon administration, converts to acompound of formula I in vivo. Also included are metabolites of thecompounds of the present invention defined as active species producedupon introduction of these compounds into a biological system.

Compounds of the invention may exist as one or more tautomers. Oneskilled in the art will recognize that compounds of formula I may alsoexist as the tautomer It as shown below.

Tautomers often exist in equilibrium with each other. As these tautomersinterconvert under environmental and physiological conditions, theyprovide the same useful biological effects. The present inventionincludes mixtures of such tautomers as well as the individual tautomersof Formula I and Formula It.

The compounds of the invention may contain one or more asymmetric carbonatoms or one or more asymmetric (chiral) centers and may thus give riseto optical isomers and diastereomers. Thus, the invention includes suchoptical isomers and disastereomers; as well as the racemic and resolved,enantiomerically pure stereoisomers; as well as other mixtures of the Rand S stereoisomers. One skilled in the art will appreciate that onestereoisomer may be more active or may exhibit beneficial effects whenenriched relative to the other stereoisomer(s) or when separated fromthe other stereoisomer(s). Additionally, the skilled artisan knows howto separate, enrich or selectively prepare said stereoisomers.Accordingly, the present invention comprises compounds of Formula I, thestereoisomers thereof, the tautomers thereof and the pharmaceuticallyacceptable salts thereof. The compounds of the invention may be presentas a mixture of stereoisomers, individual stereoisomers, or as anoptically active or enantiomerically pure form.

Preferred compounds of the invention are those compounds of formula Iwherein W is CO. Another group of preferred compounds of the inventionare those compounds of formula I wherein R₁ and R₂ are H and R₃ is C₁-C₄alkyl. Also preferred are those formula I compounds wherein n is 1. Afurther group of preferred compounds of the invention are thosecompounds of formula I wherein the nitrogen-containing 5-membered or6-membered heteroaryl ring is attached to the phenyl ring in the3-position of the phenyl ring; this preferred group of formula Icompounds is designated in the specification and claims as formula Ia.The formula Ia compound is shown below.

More preferred compounds of the invention are those compounds of formulaIa wherein the nitrogen-containing heteroaryl ring is a 6-membered ringand is attached to the phenyl ring in the 3-position of said heteroarylring; this more preferred group of formula I compounds is designated inthe specification and claims as formula Ib. Formula Ib is shown below.

Another group of more preferred compounds of the invention are thosecompounds of formula Ib wherein R₃ is methyl. A further group of morepreferred compounds of the invention are those compounds of formula Ibwherein Y is CR₁₁; R₁ and R₂ are H; and R₃ is methyl.

Examples of preferred compounds of formula I include:

-   2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5S)-2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   (5S)-2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   4-[2-amino-4-(4-methoxy-3-methylphenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-2-pyridin-3-ylbenzonitrile;-   2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(4-methyl-3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-3-ethyl-5-(4-methoxy-3-methylphenyl)-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-3-methyl-5-(3-pyrimidin-2-ylphenyl)-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(4-hydroxy-3-methylphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(3,4-diethoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(3,4-dimethoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(3-cyclopentyl-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(4-methoxy-3-propoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(3-butoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(3-isopropoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(1,3-benzodioxol-5-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(2,3-dihydro-1-benzofuran-5-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   5-[2-amino-1-methyl-5-oxo-4-(3-pyridin-3-ylphenyl)-4,5-dihydro-1H-imidazol-4-yl]-2-methoxybenzonitrile;-   2-amino-5-(3-fluoro-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(3-chloro-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-(3,4,5-trimethoxyphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyridin-4-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(3-ethoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-[(4-trifluoromethoxy-3-trifluoromethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(3,4-diethoxyphenyl)-5-(4-fluoro-3-pyridin-3-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(3-chloro-4-trifluoromethoxyphenyl)-5-(4-fluoro-3-pyridin-3-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;    a tautomer thereof; a stereoisomer thereof; or a pharmaceutically    acceptable salt thereof.

Advantageously, the present invention provides a process for thepreparation of a compound of formula I which comprises reacting acompound of formula II wherein Hal is Cl or Br with a compound offormula III wherein Q is B(OH)₂, Sn(Bu)₃ or Sn(CH₃)₃ in the presence ofa palladium catalyst and an inorganic base optionally in the presence ofa solvent. The process is shown in flow diargram I, wherein Hal and Qare as defined hereinabove.

Palladium catalysts suitable for use in the process of the inventioninclude Pd(0) or Pd(II) catalysts such asdichlorobis(tri-o-tolylphosphine)palladium(II),Pd(OCOCH₃)₂/tri-o-tolylphosphine,tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0)triphenylphosphine, or the like.

Inorganic bases suitable for use in the inventive process include Na orK hydroxides, carbonates or bicarbonates, preferably Na₂CO₃ or K₂CO₃.

Solvents suitable for use in the inventive process include polar ornon-polar organic solvents such as toluene, diethoxy ethyl ether,dioxane, ethyleneglycol dimethyl ether or any non-reactive organicsolvent which is capable of solubilizing the formula II or formula IIIcompounds.

Compounds of formula II may be prepared using conventional syntheticmethods and, if required, standard separation or isolation techniques.For example, compounds of formula II wherein W is CO and R₁ and R₂ are H(IIa), may be prepared by reacting a diketone of formula IV with asubstituted guanidine of formula V in the presence of a base such asNa₂CO₃ to give the desired compound of formula IIa. The reaction isshown in flow diagram II wherein Hal is Cl or Br.

Compounds of formula IV may be prepared by reacting atriphenylphosphonium salt of formula VI with a benzoyl chloride offormula VII in the presence of a base such as Na₂CO₃ to form thecorresponding triphenylphosphine ylide and oxidizing said ylide withKMnO₄ in the presence of MgSO₄ to give the desired diketone of formulaIV. The reaction is shown in flow diagram III wherein Hal and Hal′ areeach independently Cl or Br and Ph represents a phenyl group.

Alternatively, compounds of formula I wherein W is CO and R₁ and R₂ areH (Ic) may be prepared by reacting a diketone of formula IV with acompound of formula III in the presence of a palladium catalyst and aninorganic base to give the diketone of formula VIII and reacting saidformula VIII diketone with a substituted guanidine of formula V (asshown in flow diagram II hereinabove) to give the desired compound offormula Ic. Compounds of formula I wherein R₁ is other than H (Id) maybe prepared using standard alkylation techniques such as reacting thecompound of formula Ic with an alkyl halide, R₁-Hal, to give thecompound of formula I wherein R₁ is other than H and R₂ is H (Id). Thereaction is shown in flow diagram IV wherein Q is B(OH)₂, Sn(Bu)₃ orSn(CH₃)₃ and Hal is Cl or Br.

Compounds of formula I wherein W is CO and R₁ and R₂ are other than Hmay be prepared by reacting said formula Id compound with a second alkylhalide, R₂-Hal, to give the desired formula I compound wherein R₁ and R₂are other than H.

Advantageously, the compounds of the invention are useful for thetreatment, prevention or amelioration of a disease or disordercharacterized by elevated β-amyloid deposits or β-amyloid levels in apatient, including Alzheimer's disease, Downs Syndrome, HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch type or otherneurodegenerative or dementia-inducing disorders. Accordingly, thepresent invention provides a method for the treatment, prevention oramelioration of a disease or disorder characterized by elevatedβ-amyloid deposits or β-amyloid levels in a patient which comprisesproviding said patient with a therapeutically effective amount of acompound of formula I as described hereinabove. The compound may beprovided by oral or parenteral administration or in any common mannerknown to be an effective administration of a therapeutic agent to apatient in need thereof.

The term “providing” as used herein with respect to providing a compoundor substance embraced by the invention, designates either directlyadministering such a compound or substance, or administering a prodrug,derivative or analog which forms an equivalent amount of the compound orsubstance within the body.

As described herein, a therapeutically or prophylactically useful amountof a compound of the invention is that amount of a compound whichalleviates the symptoms of the disease, e.g., AD, or which prevents theonset of symptoms, or the onset of more severe symptoms. The usefulamounts of a compound may vary depending upon the formulation and routeof delivery. For example, higher amounts may be delivered orally thanwhen the compound is formulated for injection or inhalation, in order todeliver a biologically equivalent amount of the drug. Suitably, anindividual dose (i.e., per unit) of a compound of the invention is inthe range from about 1 μg/kg to about 10 g/kg. Desirably, these amountsare provided on a daily basis. However, the dosage to be used in thetreatment or prevention of a specific cognitive deficit or othercondition may be subjectively determined by the attending physician. Thevariables involved include the specific cognitive deficit and the size,age and response pattern of the patient. For example, based upon theactivity profile and potency of the compounds of this invention, astarting dose of about 375 to 500 mg per day with gradual increase inthe daily dose to about 1000 mg per day may provide the desired dosagelevel in the human.

In actual practice, the compounds of the invention are provided byadministering the compound or a precursor thereof in a solid or liquidform, either neat or in combination with one or more conventionalpharmaceutical carriers or excipients. Accordingly, the presentinvention provides a pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of acompound of formula I as described hereinabove.

Solid carriers suitable for use in the composition of the inventioninclude one or more substances which may also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula I.In tablets, the formula I compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula I compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) or their derivatives,or oils (e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier may also be an oily ester such as ethyloleate or isopropyl myristate.

Compositions of the invention which are sterile solutions or suspensionsare suitable for intramuscular, intraperitoneal or subcutaneousinjection. Sterile solutions may also be administered intravenously.Inventive compositions suitable for oral administration may be in eitherliquid or solid composition form.

Alternatively, the use of sustained delivery devices may be desirable,in order to avoid the necessity for the patient to take medications on adaily basis. “Sustained delivery” is defined as delaying the release ofan active agent, i.e., a compound of the invention, until afterplacement in a delivery environment, followed by a sustained release ofthe agent at a later time. Those of skill in the art know suitablesustained delivery devices. Examples of suitable sustained deliverydevices include, e.g., hydrogels (see, e.g., U.S. Pat. Nos. 5,266,325;4,959,217; and 5,292,515), an osmotic pump, such as described by Alza(U.S. Pat. Nos. 4,295,987 and 5,273,752) or Merck (European Patent No.314,206), among others; hydrophobic membrane materials, such asethylenemethacrylate (EMA) and ethylenevinylacetate (EVA); bioresorbablepolymer systems (see, e.g., International Patent Publication No. WO98/44964, Bioxid and Cellomeda; U.S. Pat. Nos. 5,756,127 and 5,854,388);other bioresorbable implant devices have been described as beingcomposed of, for example, polyesters, polyanhydrides, or lacticacid/glycolic acid copolymers (see, e.g., U.S. Pat. No. 5,817,343(Alkermes Inc.)). For use in such sustained delivery devices, thecompounds of the invention may be formulated as described herein.

In another aspect, the invention provides a pharmaceutical kit fordelivery of a product. Suitably, the kit contains packaging or acontainer with the compound formulated for the desired delivery route.For example, if the kit is designed for administration by inhalation, itmay contain a suspension containing a compound of the inventionformulated for aerosol or spray delivery of a predetermined dose byinhalation. Suitably, the kit contains instructions on dosing and aninsert regarding the active agent. Optionally, the kit may furthercontain instructions for monitoring circulating levels of product andmaterials for performing such assays including, e.g., reagents, wellplates, containers, markers or labels, and the like. Such kits arereadily packaged in a manner suitable for treatment of a desiredindication. For example, the kit may also contain instructions for useof the spray pump or other delivery device.

Other suitable components to such kits will be readily apparent to oneof skill in the art, taking into consideration the desired indicationand the delivery route. The doses may be repeated daily, weekly, ormonthly, for a predetermined length of time or as prescribed.

For a more clear understanding, and in order to illustrate the inventionmore clearly, specific examples thereof are set forth hereinbelow. Thefollowing examples are merely illustrative and are not to be understoodas limiting the scope and underlying principles of the invention in anyway. Indeed, various modifications of the invention, in addition tothose shown and described herein, will become apparent to those skilledin the art from the examples set forth hereinbelow and the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

Unless otherwise noted, all parts are parts by weight. The terms HNMRand HPLC designate proton nuclear magnetic resonance and highperformance liquid chromatography, respectively. The terms EtOAc and THFdesignate ethyl acetate and tetrahydrfuran, respectively. In thestructures, the term Ph designates a phenyl group.

EXAMPLE 1 Preparation of Ethyl 4-amino-3-bromobenzoate

A solution of bromine (7.0 mL, 137.3 mmol) in dichloromethane is addeddropwise to a cold (−10° C.) solution of ethyl 4-aminobenzoate (22.0 g,133.3 mmol) in dichloromethane. The reaction mixture is allowed to cometo room temperature, stirred for 18 h and diluted with water. Theorganic phase is separated, washed twice with brine, dried over MgSO₄and concentrated in vacuo. The resultant residue is purified by flashchromatography (SiO₂, 8/1 hexanes/EtOAc as eluent) to afford the titlecompound as a white solid, 28.6 g (88% yield), identified by HNMR andmass spectral analyses. MS m/e 242 (M−H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ1.28 (t, J=7.01 Hz, 3 H), 4.22 (q, J=7.16 Hz, 2 H), 6.18 (brs, 2 H),6.81 (d, J=7.91 Hz, 1H), 7.65 (dd, J=8.54, 1.98 Hz 1 H), 7.89 (d, J=1.83Hz, 1H).

EXAMPLE 2 Preparation of 3-Bromo-4-cyanobenzoic acid

A solution of ethyl 4-amino-3-bromobenzoate (23.5 g, 96.3 mmol) inmethylene chloride at −10° C. is treated dropwise with tert-butylnitrite (14.0 mL, 118.4 mmol), followed by boron trifluoride diethyletherate (18.4 mL, 146.5 mmol). The reaction mixture is allowed to cometo room temperature, stirred for 4 h, diluted with ethyl ether andfiltered. The filtercake is dried, dispersed in toluene, cooled to 0°C., treated with a solution of copper (I) cyanide (11.5 g, 129.2 mmol)and sodium cyanide (15.8 g, 323.1 mmol) in water, stirred at 0° C. for30 min., warmed to 60° C., stirred for 1 h, cooled to room temperatureand diluted with EtOAc and water. The organic phase is separated, driedover MgSO₄ and concentrated in vacuo. The resultant residue iscrystallized from ethyl ether/hexanes to give the ethyl ester of thetitle compound as an off-white solid, 18.6 g (76% yield). A solution ofthis ester (8.5 g, 33.6 mmol) in THF is treated with a solution of NaOH(30 mL, 2.5 N) and ethanol, stirred for 20 h, acidified with 2N HCl andextracted with ethyl ether. The ether extracts are combined, dried overMgSO₄ and concentrated in vacuo. The resultant residue is crystallizedfrom ethyl ether/hexanes to afford the title compound as a beige solid,6.81 g (90% yield), identified by HNMR and mass spectral analyses. MSm/e 223 (M−H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (dd, J=9.76, 1.37 Hz 1H), 8.09 (d, J=8.08 Hz, 1H), 8.29 (d, J=1.37 Hz, 1H).

EXAMPLE 3 Preparation of2-Bromo-4-[(4-methoxy-3-methylphenyl)(oxo)acetyl]benzonitrile

A suspension of 3-bromo-4-cyanobenzoic acid (1.65 g, 7.28 mmol) inthionyl chloride (10 mL) is treated with 3 drops ofN,N-dimethylformamide, heated at reflux temperature for 1 h andconcentrated in vacuo. This acid chloride residue is re-evaporated 3×with toluene to remove any remaining thionyl chloride. A mixture of3-methyl-4-methoxybenzyl triphenylphosphonium chloride (6.3 g, 14.55mmol) in toluene at 0° C. is treated dropwise with n-butyllithium (6.1mL, 2.5 M in hexanes), allowed to come to room temperature, stirred for2 h, cooled to 0° C., treated dropwise with a solution of theabove-obtained acid chloride in toluene, allowed to come to roomtemperature, stirred for 2 h, quenched with water and concentrated invacuo. The resultant residue is dispersed in acetone and water, treatedwith MgSO₄ (7.5 g, 62.5 mmol) and KMnO₄ (2.18 g, 13.8 mmol), vigorouslystirred at 45° C. for 18 h and filtered. The filtrate is diluted withEtOAc, washed sequentially with water and brine, dried over MgSO₄ andevaporated to dryness. This residue is purified by flash chromatography(SiO₂, 2/1 hexanes/EtOAc as eluent) to afford the title compound as ayellow solid, 1.8 g (69% yield), identified by HNMR and mass spectralanalyses. MS m/e 357 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 2.21 (s, 3H),3.93 (s, 3H), 7.15 (d, J=8.54 Hz, 1H), 7.81 (d, J=1.38 Hz, ₁H),7.85 (dd,J=8.54, 2.14 Hz, 1H), 8.03 (dd, J=8.08, 1.52 Hz 1 H), 8.18 (d, J=8.08Hz, 1H), 8.30 (d, J=1.38 Hz, 1H).

EXAMPLE 4 Preparation of4-[(4-Methoxy-3-methylphenyl)(oxo)acetyl]-2-pyridin-3-ylbenzonitrile

A mixture of2-bromo-4-[(4-methoxy-3-methylphenyl)(oxo)acetyl]benzonitrile (200 mg,0.56 mmol) and 3-(tributylstannyl)pyridine (268 mg, 0.73 mmol) in1,2-diethoxyethane is treated withdichlorobis(tri-o-tolylphosphine)palladium(II) (39.6 mg, 0.05 mmol),heated at 145° C., stirred for 30 min. and filtered to remove thecatalyst. The filtrate is evaporated to dryness. The resultant residueis purified by flash chromatography (SiO₂, 2/1 hexanes/EtOAc as eluent)and crystallization from ethyl ether/hexanes to afford the titlecompound as a yellow solid, 181 mg (91% yield), identified by HNMR andmass spectral analyses. MS m/e 357 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ2.21 (s, 3H), 3.93 (s, 3H), 7.18 (d, J=8.69 Hz, 1H), 7.61 (m, 1H), 7.82(d, J=8.54, 1H), 7.84 (dd, J=8.54, 1.99 Hz 1 H), 8.07 (dd, J=7.76, 1.67Hz, 1H), 8.12 (m, J=1.38 Hz, 2H), 8.25 (d, J=8.08 Hz, 1H), 8.74 (m, 1H),8.85 (d, 1.68 Hz, 1H).

EXAMPLE 5 Preparation of4-[2-amino-4-(4-methoxy-3-methylphenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-2-pyridin-3-ylbenzonitrile

A mixture of4-[(4-methoxy-3-methylphenyl)(oxo)acetyl]-2-pyridin-3-ylbenzonitrile(160 mg, 0.45 mmol) and 1-methylguanidine hydrochloride (222 mg, 2.02mmol) in dioxane and ethyl alcohol is treated with Na₂CO₃ (214 mg, 2.02mmol) in water, stirred at 85° C. for 3 h and concentrated in vacuo. Theresultant residue is partitioned between chloroform and water. Thephases are separated and the organic phase is dried over MgSO₄ andconcentrated in vacuo. This residue is purified by flash chromatography(SiO₂, 15/1 EtOAc/methanol as eluent) and crystallization fromCHCl₃/hexanes to give the title compound as a white solid, 138 mg (75%yield), identified by HNMR and mass spectral analyses. MS m/e 412(M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 2.09 (s, 3H), 2.98 (s, 3H), 3.74 (s,3H), 6.74 (brs, 2H), 6.86 (d, J=8.69 Hz, 1H), 7.22 (s, 1H), 7.26 (d,J=8.54 Hz, 1H), 7.58 (m, 1H), 7.69 (s, 1H), 7.70 (s, 1H), 7.9-8.0 (m,2H), 8.7 (m, 2H).

EXAMPLES 6-33 Preparation of Amino-5,5-diphenylimidazolone Derivatives

Using essentially the same procedures described in Examples 4 and 5hereinabove and employing the appropriate dione substrate,tributylstannyl-pyridine or -pyrimidine intermediate and desiredguanidine reagent, the compounds shown on Table I are obtained andidentified by HNMR and mass spectral analyses. TABLE I

Ex. No R₃ R₄ R₅ R₆ R₇ X Y mp ° C. 6 CH₃ 3-CH₃ 4-OCH₃ H 4-CH₃ CH CH — 7CH₃ 3-CF₃ 4-OCH₃ H H CH CH — 8 C₂H₅ 3-CH₃ 4-OCH₃ H H CH CH — 9 CH₃ 3-HC₃4-OCH₃ H H CH N — 10 CH₃ 3-CH₃ 4-OH H H CH CH — 11 CH₃ 3-CF₃ 4-OCH₃ H HCH N — 12 CH₃ 3-CH₃ 4-OCH₃ H H N CH 126 13 CH₃ 3-CH₃ 4-OCH₃ H H CH CH117-120 14 CH₃ 3-OCH₃ 4-OCH₃ H H CH CH 108-111 15 CH₃ 3-cyclopentyl4-OCH₃ H H CH CH 105-110 16 CH₃ 3-OC₃H₇ 4-OCH₃ H H CH CH 103-106 17 CH₃3-OC₄H₉ 4-OCH₃ H H CH CH  97-100 18 CH₃ 3-OCH(CH₃)₂ 4-OCH₃ H H CH CH106-109 19 CH₃ 3-Ocyclopentyl 4-OCH₃ H H CH CH 117-120 20 CH₃ 3-CN4-OCH₃ H H CH CH 140-143 21 CH₃ 3-F 4-OCH₃ H H CH CH 111-114 22 CH₃ 3-Cl4-OCH₃ H H CH CH 112-116 23 CH₃ 3-OCH₃ 4-OCH₃ 5-OCH₃ H CH CH 104-107 24CH₃ 3-OC₂H₅ 4-OCH₃ H H CH CH 125 25 CH₃ 3-OCF₃ H H H CH CH 198 26 CH₃3-CF₃ 4-OCF₃ H H CH CH  98 27 CH₃ 3-OC₂H₅ 4-OC₂H₅ H 4-F CH CH  99-100 28CH₃ 3-Cl 4-OCF₃ H 4-F CH CH  99-102 29 CH₃ 3-OC₂H₅ 3-OC₂H₅ H H CH CH95-99 30 CH₃ 3-O—CH₂—O-4- H H CH CH 104-106 31 CH₃ 3-CH₂—CH₂—O-4 H H CHCH 122-126 32 CH₃ 3-O—CH₂CH₂—O-4- H H CH CH 157-160 33 H H 4-OCF₃ H 4-FH CH —

EXAMPLE 34 Preparation of2-Amino-3-difluoromethyl-5-[4-fluoro-3-(pyrimidin-5-yl)phenyl]-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4one

A solution of2-amino-5-[4-fluoro-3-(pyrimidin-5-yl)phenyl]-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one(0.398 g, 0.92 mmol) in dimethylformamide is treated with KOH (0.057 g,1.01 mmol), cooled to −45° C., and bubbled with chlorodifluoromethane(1.40 g, 17.6 mmol). The reaction vessel is sealed and heated at 70° C.for 18 h. The reaction is cooled to room temperature, quenched bycareful addition to water, extracted with ethyl acetate, diluted withbrine and extracted again with ethyl acetate. The combined extracts arewashed with brine, dried over sodium sulfate and concentrated. Theresultant residue is purified twice by flash chromatography (silica,95:5:0.5 to 90:10:0.5 methylene chloride/methanol/concentrated ammoniumhydroxide and 100:0 to 98:2 methylene chloride/methanol as eluents) toafford the title compound as a white solid, 0.064 g (14% yield), mp82-94° C., identified by HNMR, infrared and mass spectral analyses. ¹HNMR (500 MHz, CDCl₃) δ 9.21 (s,1H), 8.89 (s, 2H), 7.64-7.60 (m, 2H),7.54 (d, J=8.8 Hz, 2H), 7.23-7.18 (m, 3H), 6.95 (t, J=58 Hz, 1H), 4.92(br s, 2H); IR (ATR) 3497, 3309, 3149, 1761, 1678, 1497, 1449, 1416,1252, 1212, 1162 cm⁻¹; ESI MS m/z 482 [C₂₁H₁₃F₆N₅O₂+H]⁺;

EXAMPLE 35 Preparation of1-(4-Methoxy-3-methylphenyl)-2-(3-pyridin-4-ylphenyl)ethane-1,2-dione

A solution of1-(3-bromo-phenyl)-2-(4-methoxy-3-methylphenyl)ethane-1,2-dione (0.25 g,0.75 mmol) in dioxane is treated sequentially with tri-o-tolylphosphine(57 mg, 0.187 mmol), palladium (II) acetate (21 mg, 0.093 mmol),pyridine-4-boronic acid (139 mg, 1.125 mmol) and H₂O, stirred at 100° C.for 4 h, cooled to room temperature and filtered. The filtrate isevaporated in vacuo. The resultant residue is purified by flashchromatography on silica gel (hexanes/EtOAc 3/7 as eluent), to affordthe title compound as a yellow solid, 0.145 g (58% yield), identified byHNMR and mass spectral analyses. MS m/e (M+H)⁺ 332; ¹H NMR (400 MHZ,CDCl₃) δ 2.28 (s, 3H) 3.95 (s, 3H) 6.94 (d, 1H) 7.68 (m, 3H) 7.84 (m,2H) 7.88 (m, 1H) 8.08 (m, 1H) 8.30 (m, 1H) 8.75 (m, 2H).

EXAMPLE 36 Preparation of2-Amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyridin-4-ylphenyl)-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 5 hereinabove,and employing1-(4-methoxy-3-methylphenyl)-2-(3-pyridin-4-ylphenyl)ethane-1,2-dioneand 1-methylguanidine hydrochloride as reactants, the title compound isobtained as a white solid, 0.15 g (90% yield), mp 175° C., identified byHNMR and mass spectral analyses. MS m/e (M)⁺387; ¹H NMR (400 MHZ,DMSO-d₆) δ 2.05 (s, 3H) 3.00 (s, 3H) 3.75 (s, 3H) 6.60 (bs, 2H) 6.82 (d,1H) 7.20 (m, 1H) 7.25 (m, 1H) 7.40 (m, 1H) 7.50 (m, 3H) 7.62 (m, 1H) 7.8(m, 1H) 8.6 (m, 2H).

EXAMPLE 37 Preparation of2-Amino-3-methyl-5-(3-pyrimidin-2-ylphenyl)-5-[4-(trifluoromethoxy)phenyl]-3.5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 36 hereinaboveand employing1-(3-pyrimidin-2-ylphenyl)-2-[4-(trifluoromethoxy)phenyl]ethane-1,2-dioneand methylguanidine hydrochloride as reactants, the title compound isobtained as a white solid, identified by HNMR and mass spectralanalyses. MS m/e 428 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 3.01 (s, 1H),6.79 (brs, 2H), 7.33-7.49 (m, 2H), 7.58-7.66 (m, 3H), 8.27 (m, 2H), 7.59(d, J=7.77 Hz, 1H), 7.98 (d, J=7.47 Hz, 1H), 8.26 (s, 1H), 8.61 (t,J=1.67 Hz, 1H), 8.90 (d, J=4.88 Hz, 2H).

EXAMPLE 38 Preparation of(5R)-2-Amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one(A) and(5S)-2-Amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one(B)

Racemic2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-oneis resolved using chiral HPLC technique on a Chiralcel AD, 2×25 cm andusing as mobile phase 50% IPA/DEA in 7200/DEA with a flow rate of 10mL/min. The R-isomer, title compound A, is obtained, aftercrystallization from chloroform/hexane as a white solid, 98% ee;identified by HNMR and mass spectral analyses. MS m/e 388 (M+H)⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 2.07 (s, 3H), 2.97 (s, 3H), 3.72 (s, 3H), 6.63(brs, 2H), 6.85 (d, J=8.39 Hz, 1H), 7.21 (s, 1H), 7.25 (dd, J=7.88,1.01, 1H), 7.46 (t, J=7.55 Hz, 1H), 7.52 (d, J=7.89 Hz, 1H), 7.63 (dd,J=7.54, 0.84 Hz, 1H), 7.75 (s, 1H), 8.99 (s, 2H), 9.18 (s, 1H).

[α]_(D) ²⁵=+40.2 (c=1% in CH₃OH)

The S-isomer, title compound B, is obtained, after crystallization fromchloroform/hexane as a white solid, 95% ee; identified by HNMR and massspectral analyses. MS m/e 388 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 2.07(s, 3H), 2.97 (s, 3H), 3.72 (s, 3H), 6.63 (brs, 2H), 6.85 (d, J=8.39 Hz,1H), 7.21 (s, 1H), 7.25 (dd, J=7.88, 1.01, 1H), 7.46 (t, J=7.55 Hz, 1H),7.52 (d, J=7.89 Hz, 1H), 7.63 (dd, J=7.54, 0.84 Hz, 1H), 7.75 (s, 1H),8.99 (s, 2H), 9.18 (s, 1H).

[α]_(D) ²⁵=−79.6 (c=0.67% in CH₃OH)

Absolute configuration for each of title compound A and B is determinedby x-ray crystallography.

EXAMPLE 39 Preparation of2-Amino-5-(3-bromo-4-fluorophenyl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]-3-methyl-3,5-dihydroimidazol-4-one

A mixture of1-(3-bromo-4-fluorophenyl)-2-[3-fluoro-4-(trifluoromethoxy)-phenyl]ethane-1,2-dione(0.594 g, 1.45 mmol) and 1-methylguanidine hydrochloride (0.716 g, 6.53mmol) in dioxane and ethanol is stirred at room temperature for 5 min.,treated with a solution of sodium carbonate (0.692 g, 6.53 mmol) inwater (5 mL), heated at 85° C. with stirring for 45 min., cooled to roomtemperature, and concentrated in vacuo. The resultant residue ispartitioned between methylene chloride and water. The organic phase isseparated, washed with sequentially with water and brine, dried oversodium sulfate and concentrated in vacuo. This residue is purified byflash chromatography (silica, 95:5:0.5 methylenechloride/methanol/concentrated ammonium hydroxideas eluent) to afford aviscous oil. This oil is dissolved in a minimal amount of methylenechloride, treated with hexanes and then concentrated to afford the titleproduct as an off-white solid, 0.30 g (45% yield), identified by HNMRand mass spectral analyses. ¹H NMR (500 MHz, CD₃OD) δ 7.64 (dd, J=6.6,2.2 Hz, 1H), 7.43-7.37 (m, 2H), 7.33 (dd, J=11.5, 2.1 Hz, 1H), 7.30 (m,1H), 7.18 (t, J=8.6 Hz,1 H), 3.11 (s, 3H); ESI MS m/z 464[C₁₇H₁₁BrF₅N₃O₂+H]⁺.

EXAMPLE 40 Preparation of2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]-3-methyl-3,5-dihydro-imidazol-4-one

A mixture of ethylene glycol dimethyl ether,tris(dibenzylideneacetone)-dipalladium(0) (0.015 g, 16.5 μmol) andtriphenylphosphine (0.008 g, 32.0 μmol) under nitrogen is stirred for 5min, treated with2-amino-5-(3-bromo-4-fluorophenyl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]-3-methyl-3,5-dihydroimidazol-4-one(0.154 g, 0.33 mmol), 5-pyrimidine boronic acid (0.046 g, 0.37 mmol),sodium carbonate (0.105 g, 0.99 mmol) and water, heated at refluxtemperature for 1.25 h, cooled to room temperature and concentrated invacuo. The resultant residue is purified by flash chromatography(silica, 95:5:0.5 methylene chloride/methanol/concentrated ammoniumhydroxide as eluent) to afford a viscous oil. This oil is suspended in amixture of methylene chloride/hexanes and concentrated to afford thetitle compound as an off-white solid, 0.045 g (29% yield), mp 102-110°C., identified by HNMR and mass spectral analyses. ¹H NMR (500 MHz,CD₃OD) δ 9.15 (s,1H), 8.95 (s, 2H), 7.62-7.56 (m, 2H), 7.39-7.27 (m,4H), 3.12 (s, 3H); IR 3353, 3061, 2956, 1732, 1668, 1498, 1470, 1416,1251, 1216, 1170 cm⁻¹; ESI MS m/z 464 [C₂₁H₁₄F₅N₅O₂+H]⁺; HPLC (Method 2)95.0% (AUC) t_(R)=13.78 min.

EXAMPLE 41 Preparation of2-Amino-5-[4-fluoro-3-(5-fluoropyridin-3-yl)phenyl]-5-[3-fluoro-4-(trifluoromethoxy)phenyl]-3-methyl-3,5-dihydro-imidazol-4-one

A mixture of2-amino-5-(3-bromo-4-fluorophenyl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]-3-methyl-3,5-dihydroimidazol-4-one(0.17 g, 0.366 mmol), 5-fluorpyridin-3-yl-tri(n-butyl)stannate (0.212 g,0.55 mmol) and bis(triphenylphosphino)palladium(II) chloride (0.013 g,0.018 mmol) in dimethyl formamide is degassed, heated at 150° C. for 1h, cooled to room temperature and diluted with ethyl acetate and 2%aqueous lithium chloride. The organic phase is separated, washed with 2%aqueous lithium chloride, dried over sodium sulfate and concentrated invacuo. Purification of the resultant residue by flash chromatography(silica, 97:3:0.25 methylene chloride/methanol/concentrated ammoniumhydroxide as eluent) affords the title compound as a white solid, 0.130g (74% yield), mp 91-97° C.; identified by HNMR and mass spectralanalyses. ¹H NMR (300 MHz, CD₃OD) 8.55 (m, 1H), 8.49 (d, J=3.0 Hz, 1H),7.83 (d, J=9.6 Hz, 1H), 7.60-7.21 (m, 6H), 3.13 (s, 3H); IR (ATR) 3352,3070, 1732, 1669, 1598, 2502, 1479, 1421, 1252, 1217, 1171, 883, 817,794, 703 cm⁻¹; ESI MS m/z 481

EXAMPLES 42-99 Preparation of 2-Amino-5,5-diphenylimidazoloneDerivatives

Using essentially the same procedures described hereinabove for examples40 and 41 and employing the appropriate2-amino-5-(3-bromophenyl)-5-(substituted-phenyl)imidazolone substrateand pyridinyl or pyrimidinyl reagent, the compounds shown on Table IIwere obtained and identified by HNMR and mass spectral analyses. TABLEII

Ex. No R₄ R₅ R₇ R₉ R₈ X mp ° C. 42 3-F 4-OCF₃ 4-F H H C—Cl 201-203 433-F 4-OCF₃ 4-F F H CH 75-80 44 3-OC₂H₅ 4-OC₂H₅ H H H N 100-105 46 H4-OCF₃ 4-F H H C—Cl 241-243 47 H 4-OCF₃ 4-F H H C—F 216-218 48 H 4-OCF₃2-F H H N 130-135 49 H 4-OCF₃ 4-Cl H H N 124-129 50 H 4-OCF₃ 4-F H H CH134 51 H 4-OCF₃ H H H 3—OCH₃ 212 52 H 4-OCF₃ H OCH₃ H CH  96 53 H 4-OCF₃3-F H H N 226 54 3-CH₃ 4-OCH₃ 4-F H H N 116 55 3-CH₃ 4-OCH₃ 4-F F H CH113 56 3-CF₃ 4-OCH₃ 4-F H H N 115 57 3-CF₃ 4-OCH₃ 4-F H 6-F CH 135 583-CF₃ 4-OCH₃ 4-F F H CH 118 59 3-CH₃ 4-OCH₃ H F H CH 125 60 H 4-OCH₃ 4-FH H C—F — 61 3-CH₃ 4-OCH₃ 4-F H H C—F — 62 H 4-OCH₃ 4-F F H CH — 63 H4-OCH₃ 4-F H H N — 64 H 4-OCF₃ H H 6-OCH₃ CH — 65 H 4-OCF₃ H H 6-F CH —66 H 4-OCF₃ H F H CH — 67 3-OC₂H₅ 4-OC₂H₅ H H H C—OCH₃ — 68 3-OC₂H₅4-OC₂H₅ H OCH₃ H CH — 69 3-OC₂H₅ 4-OC₂H₅ H H 6-F CH — 70 3-OC₂H₅ 4-OC₂H₅H F H CH — 71 H 4-OCF₃ 4-F H H C—OCH₃ — 72 H 4-OCF₃ 4-F OCH₃ H CH — 73 H4-OCF₃ 4-F H 6-F CH — 74 H 4-OCF₃ 4-F F H CH — 75 3-CH₃ 4-OCH₃ H OCH₃ HCH — 77 H 4-OCF₃ 4-F H H N — 78 3-F 4-OCF₃ 4-F H 4-F CH 93-96 79 3-C₂H₅3-C₂H₅ 4-F F H CH  95-100 80 H 4-OCH₃ 4-F H H C—Cl — 81 3-OC₂H₅ 4-OC₂H₅H H 4-F CH — 82 H 4-OCF₃ H H 4-F CH — 83 H 4-OCH₃ 4-F H 4-F CH — 84 H4-OCF₃ 6-F H H CH — 85 H 4-OCF₃ 2-F H H CH 239 86 3-OC₂H₅ 4-OC₂H₅ 4-F HH N 95-98 87 H 4-OCHF₂ 4-F H H C—F — 88 H 4-OCHF₂ 4-F H 6-F CH — 89 H4-OCHF₂ H F H CH — 90 H 4-OCHF₂ H H 6-F CH — 91 H 4-OCHF₂ H F H C—F — 92H 4-OCHF₂ 4-F F H C—F — 93 H 4-SCF₃ 4-F F H CH  95 94 H 4-SCF₃ 4-F H H N183 95 H 4-OCHF₂ 4-F H H CH 104-106 96 H 4-OCHF₂ 4-F F H CH 108-110 97 H4-OCHF₂ 4-F H H N 103-105 99 3-OC₂H₅ 4-OC₂H₅ 4-F H H CH 93-95

EXAMPLE 100 Preparation of2-Amino-5-[4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl]3-methyl-5-[4-(trifluoromethoxy)phenyl]-3.5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 41 hereinaboveand employing2-amino-5-(3-bromo-4-fluorophenyl)-3-methyl-5-[4-(trifluoromethoxy)phenyl-3,5-dihydro-4H-imidazol-4-oneand 1-methyl-4-(tributylstannyl)-1H-pyrazole as reactants, the titleproduct is obtained as a white solid, identified by HNMR and massspectral analyses. ¹H NMR (300 MHz, DMSOd₆) δ 2.95 (s, 3H), 3.92 (s,3H), 6.7 (brs, 2H), 7.15 (t, 1H), 7.28 (m, 3H), 7.5 (m, 2H), 7.65 (m,2H), 8.0 (d, 1H) MS m/e (M+H)⁺ 448

EXAMPLE 101 Preparation of(5S)-2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4one(A) and(5R)-2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-]4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one(B)

Racemic2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-oneis resolved using chiral HPLC technique on a Chiralcel AD, 2×25 cm andusing as mobile phase EtOH with a flow rate of 11 mL/min. The S-isomer,title compound A, is obtained, after crystallization fromchloroform/hexanes, as a white solid, 98.8% ee; identified by HNMR andmass spectral analyses. ¹H NMR (300 MHz, DMSOd₆) δ 2.95 (s, 3H), 3.95(m, 4H), 6.72 (brs, 2H), 7.25 (d, 2H), 7.32 (t, 1H), 7.55-7.6 (m, 3H),7.65 (dd, 1H), 8.9 (s, 2H), 9.2 (s, 1H) MS m/e (M+H)⁺ 446

The R-isomer, title compound B, is obtained, after crystallization fromchloroform/hexanes, as a white solid, 98.4% ee; identified by HNMR andmass spectral analyses. ¹H NMR (300 MHz, DMSOd₆) δ 2.95 (s, 3H), 3.95(m, 4H), 6.72 (brs, 2H), 7.25 (d, 2H), 7.32 (t, 1H), 7.55-7.6 (m, 3H),7.65 (dd, 1H), 8.9 (s, 2H), 9.2 (s, 1H) MS m/e (M+H)⁺ 446

EXAMPLE 102 Preparation of(5R)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(A) and(5S)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(B)

Racemic2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-oneis resolved using chiral HPLC technique on a Chiralcel AD, 2×25 cm andusing as mobile phase 9% EtOH/DEA in hexane/DEA with a flow rate of 25mL/min. The R-isomer, title compound A, is obtained, aftercrystallization from chloroform/hexanes, as a white solid, 100% ee;identified by HNMR and mass spectral analyses. ¹H NMR (300 MHz, DMSOd₆)δ 2.05 (s, 3H), 2.96 (s, 3H), 3.67 (s, 3H), 6.62 (brs, 2H), 6.6 (d, 1H), 7.25-7.35 (m, 2H), 7.35-7.5 (m, 2H), 7.65 (m, 1H), 7.95 (m, 2H), 8.4(dd, 1H)

MS m/e (M+H)⁺ 405 [α]_(D) ²⁵=+22 (c=1% in CH₃OH)

The S-isomer, title compound B, is obtained, after crystallization fromchloroform/hexanes, as a white solid, 98% ee; identified by HNMR andmass spectral analyses. ¹H NMR (300 MHz, DMSOd₆) δ 2.05 (s, 3H), 2.96(s, 3H), 3.67 (s, 3H), 6.62 (brs, 2H), 6.6 (d, 1H), 7.25-7.35 (m, 2H),7.35-7.5 (m, 2H), 7.65 (m, 1H), 7.95 (m, 2H), 8.4 (dd, 1H)

MS m/e (M+H)⁺ 405 [α]_(D) ²⁵=−9.5 (c=0.4% in CH₃OH)

EXAMPLE 103 Preparation of(5R)-2-Amino-5-(3,4-diethoxyphenyl)-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(A) and(5S)-2-Amino-5-(3,4-diethoxyphenyl)-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(B)

Racemic2-amino-5-(3,4-diethoxyphenyl)-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-oneis resolved using chiral HPLC technique on a Chiralcel AD, 0.46×25 cmcolumn and using as mobile phase 25% EtOH in hexanes/DEA. The R-isomer,title compound A, is obtained and identified by HNMR and mass spectralanalyses. ¹H NMR (DMSOd₆ 300 MHz) δ 1.22 (m, 6H), 2.95 (s, 3H), 3.95 (m,4H), 6.6 (brs, 2H), 6.85 (d, 1H), 7.0 (m, 2H), 7.37-7.45 (m, 3H), 7.48(d, (d, 1H), 7.63 (s, 1H), 7.96 (m, 1H), 8.2 (d, 1H) MS m/e (M+H)⁺ 449

[α]_(D) ²⁵=+7.4 (c=1% in CH₃OH)

The S-isomer, title compound B, is obtained and identified by HNMR andmass spectral analyses. ¹H NMR (DMSOd₆ 300 MHz) δ 1.22 (m, 6H), 2.95 (s,3H), 3.95 (m, 4H), 6.6 (brs, 2H), 6.85 (d, 1H), 7.0 (m, 2H), 7.37-7.45(m, 3H), 7.48 (d, 1H), 7.63 (s, 1H), 7.96 (m, 1H), 8.2 (d, 1H) MS m/e(M+H)⁺ 449

[α]_(D) ²⁵=−9.8 (c=1% in CH₃OH)

EXAMPLE 104 Preparation of2-Amino-5-[3,4-bis-(2-fluoro-ethoxy)-phenyl]-5-[4-fluoro-3-(2-fluoro-pyridin-3-yl)-phenyl]-3-methyl-3,5-dihydro-imidazol-4-one

Step a) Preparation of Compound 2

Sodium hydride (1.82 g of a 60% dispersion in oil, 45.5 mmol) was washedwith hexanes, suspended in DMF (5 mL) and treated dropwise with asolution of 1 (2.0 g, 13.0 mmol) in DMF (15 mL) over a period of 10 minat room temperature. After stirring for an additional 1.5 h at roomtemperature, the mixture was treated with a solution of 1-bromo-2-fluoroethane in DMF (15 mL) and the mixture stirred at room temperature for 18h, then heated at 60° C. for an additional 4 h. The mixture was cooledto room temperature and diluted with ethyl acetate (100 mL) and water(100 mL). The organic layer was separated and washed with 1 N NaOH (100mL), 5% aqueous lithium chloride (2×100 mL), brine (100 mL), dried overmagnesium sulfate, filtered and concentrated. Purification by flashchromatography (silica, 1:3 ethyl acetate/hexanes) afforded 2 (1.00 g,26%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.74 (dd, J=8.4, 2.0Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.84 (m, 2H),4.75 (m, 3H), 4.67 (m, 1H), 4.58 (m, 1H), 4.52 (m, 1H), 4.36 (m, 2H),4.30 (m, 2H); ESI MS m/z 293 [C₁₃H₁₅F₃O₄+H]⁺.

Step b) Preparation of Compound 3

A mixture of 2 (1.00 g, 3.42 mmol) in ethanol (10 mL) and 1 N NaOH (10mL) was heated at 75° C. for 1 h. The mixture was cooled to roomtemperature, concentrated, diluted with water (10 mL) and acidified with6 N HCl. The solids that formed were collected by filtration and driedto afford 3 (0.76 g, 90%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ12.8 (br s, 1H), 7.58 (dd, J=8.4, 1.5 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H),7.11 (d, J=8.5 Hz, 1H), 4.84 (m, 2H). 4.67 (m, 2H), 4.39-4.22 (m, 4H).

Step c) Preparation of Compound 4

A mixture of 3 (0.76 g, 3.09 mmol), thionyl chloride (8 mL) and DMF (1drop) was heated at reflux for 4 h. The mixture was then cooled to roomtemperature and concentrated. The residue was dissolved in toluene andagain concentrated to afford 4 (0.82 g, 100%) as a white solid: ¹H NMR(300 MHz, CDCl₃) δ 7.85 (dd, J=8.4, 1.8 Hz, 1H), 7.62 (d, J=2.1 Hz, 1H),6.98 (d, J=8.7 Hz, 1H), 4.89 (m, 2H). 4.75 (m, 2H), 4.43-4.26 (m, 4H);IR (ATR) 1734, 1582, 1513, 1417 cm⁻¹.

Step d) Preparation of Compound 6

A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran(3.25 mL, 3.25 mmol) was added to a stirred suspension of(3-bromo-4-fluorobenzyl)triphenylphosphonium bromide (1.72 g, 3.25 mmol)in tetrahydrofuran (6 mL). The mixture was stirred for 25 min at roomtemperature, then cooled to −40° C., treated with a solution of 4 (0.82g, 3.10 mmol) in tetrahydrofuran (3 mL) and stirred for an additional 2h while slowly warming to room temperature. The reaction was thentreated with water (5 mL) and sodium periodate (0.69 g, 3.25 mmol), thenheated at 50° C. for 19 h. After this time the mixture was cooled toroom temperature and diluted with ethyl acetate (25 mL). The organiclayer was separated and washed with water (10 mL) and brine (10 mL),dried over magnesium sulfate, filtered and concentrated. Purification byflash chromatography (silica, 1:3 ethyl acetate/hexanes) afforded 6(0.27 g, 20%) as a pale yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.22(dd, J=6.5, 2.1 Hz, 1H), 7.92 (m, 1H), 7.63 (d, J=2.0 Hz), 7.51 (dd,J=8.4, 2.9 Hz, 1H), 7.23 (m, 1H), 7.96 (d, J=8.5 Hz, 1H) 4.85 (m, 2H),4.76 (m, 2H), 4.39-4.31 (m, 4H).

Step e) Preparation of Compound 7

A mixture of 6 (0.26 g, 0.603 mmol) and 1-methylguanidine hydrochloride(0.30 g, 2.71 mmol) in dioxane (8 mL) and ethanol (5.3 mL) was stirredat room temperature for 5 min. A solution of sodium carbonate (0.29 g,2.71 mmol) in water (2.3 mL) was then added and the mixture immersedinto an 85° C. oil bath and stirred for 30 min. The reaction mixture wascooled to room temperature, concentrated and the residue partitionedbetween methylene chloride (50 mL) and water (20 mL). The organic layerwas separated, washed with water (20 mL), brine (20 mL), dried overmagnesium sulfate, filtered and concentrated. Purification by flashchromatography (silica, 95:5:0.5 methylenechloride/methanol/concentrated ammonium hydroxide) afforded 7 (0.154 g,53%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.68 (m, 1H), 7.33 (m,1H), 7.07 (m, 3H), 6.89 (m, 1H), 4.80 (m, 2H), 4.66 (m, 2H), 4.28 (m,2H), 4.18 (m, 2H); ESI MS m/z 486 [C₂₀H₁₉BrF₃N₃O₃+H]⁺.

Step f) Preparation of2-amino-5-[3,4-bis-(2-fluoro-ethoxy)-phenyl]-5-[4-fluoro-3-(2-fluoro-pyridin-3-yl)-phenyl]-3-methyl-3,5-dihydro-imidazol-4-one

A mixture of 7 (0.140 g, 0.288 mmol), 2-fluoropyridine-3-boronic acid(0.061 g, 0.430 mmol), sodium carbonate (0.092 g, 0.860 mmol),bis(triphenylphosphino)palladium (II)chloride (0.010 g, 0.014 mmol) andtriphenylphosphine (0.008 g, 0.028 mmol) in 1:1 toluene/ethanol (8 mL)was degassed and heated at 110° C. for 1.5 h. The mixture was cooled toroom temperature, concentrated and purified by flash chromatography(silica, 97:3:0.25 methylene chloride/methanol/concentrated ammoniumhydroxide) to afford 8 (0.055 g, 39%) as a white solid, mp 85-95° C.; ¹HNMR (300 MHz, CD₃OD) δ 8.23 (m, 1H), 7.93 (m, 1H), 7.51-7.38 (m, 3H),7.21 (t, J=9.0 Hz, 1H), 6.98 (m, 3H), 4.78 (m, 2H), 4.68 (m, 2H),4.62-4.58 (m, 4H), 3.11 (s, 3H); IR (ATR) 1733, 1666, 1502, 1260 cm⁻¹;ESI MS m/z 503 [C₂₅H₂₄F₄N₄O₃+H]⁺. Anal. Calcd for C₂₅H₂₄F₄N₄O₃.0.25H₂O:C, 59.28; H, 4.45; N, 10.73. Found: C, 59.23; H, 4.47; N, 11.05.

EXAMPLE 105 Preparation of(5S)-2-Amino-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

The racemate2-amino-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by HPLC using Chiralcel OJ, 2×25 cm, mobile phase 15%EtOH/DEA in hexaneand a flow rate of 21 mL/min to give the title Sisomer (A), ¹H NMR (DMSOd₆ 300 MHz) δ 2.0 (s, 3H), 2.95 (s, 3H), 3.7 (s,3H), 6.6 (b, 2H), 6.8 (d, 1H), 7.3 (m, 3H), 7.5 (m, 3H), 8.0 (m, 1H),8.3 (m, 1H); MS m/e (M)⁺ 423; [α]₂₅=+76.4 (C=1% in MeOH); mp 103-105 C.°and the title R isomer (B), ¹H NMR (DMSOd₆ 300 MHz) δ 2.0 (s, 3H), 2.95(s, 3H), 3.7 (s, 3H), 6.6 (b, 2H), 6.8 (d, 1H), 7.3 (m, 3H), 7.5 (m,3H), 8.0 (m, 1H), 8.3 (m, 1H); MS m/e (M)⁺ 423; [α]₂₅=−40.8 (C=1% inMeOH); mp 103-105 C.°.

EXAMPLE 106 Preparation of (5S)2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

The racemate2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by HPLC using Chiralcel OD, 2×25 cm, mobile phase cm usingmobile phase MeOH (30% with 0.1% DEA) in CO₂ (100 bar) and a flow rateof 50 mL/min to give the title S isomer (A), ¹H NMR (400 MHZ, DMSO-d₆) δ2.04 (s, 3H), 2.93 (s, 3H), 3.69 (s, 3H), 6.61 (bs, 2H), 6.81 (m, 1H),7.22 (m, 1H), 7.27 (m, 1H), 7.29 (m, 1H), 7.60 (m, 1H), 7.61 (m, 1H),8.89 (d, 2H), 9.18 (d, 1H); MS m/e (M+H)⁺ 406; mp 115° C.; [α]₂₅=48(C=1% in MeOH); and the title R isomer (B), ¹H NMR (400 MHZ, DMSO-d₆) δ2.04 (s, 3H), 2.93 (s, 3H), 3.69 (s, 3H), 6.60 (bs, 2H), 6.81 (m, 1H),7.22 (m, 1H), 7.27 (m, 1H), 7.29 (m, 1H), 7.60 (m, 1H), 7.61 (m, 1H),8.89 (d, 2H), 9.18 (d, 1H); MS m/e (M+H)⁺ 406; mp 115° C.; [α]₂₅=−39.2(C=1% in MeOH).

EXAMPLE 107 Preparation of(5S)-2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by HPLC using Chiralcel OD, 2×25 cm, mobile phase cm,mobile phase EtOH/Hexane (15/85) and a flow rate of 20 mL/min to givethe title S isomer (A), ¹H NMR (400 MHZ, DMSO-d₆) δ 2.94 (s, 3H), 3.81(s, 3H), 6.76 (bs, 2H), 7.19 (m, 1H), 7.32 (m, 1H), 7.32 (m, 1H), 7.50(m, 1H), 7.70 (m, 2H), 8.89 (d, 2H), 9.18 (d, 1H); MS m/e (M+H)⁺ 460.1;mp 100° C; [α]₂₅=1.6 (C=1% in MeOH); and the title R isomer (B), ¹H NMR(400 MHZ, DMSO-d₆) δ 2.94 (s, 3H), 3.81 (s, 3H), 6.76 (bs, 2H), 6.82 (m,1H), 7.22 (m, 1H), 7.32 (m, 1H), 7.50 (m, 1H), 7.59 (m, 1H), 7.70 (m,1H), 8.89 (d, 2H), 9.18 (d, 1H); MS m/e (M−H)⁻ 458; mp 100° C.;[α]₂₅=−1.8 (C=1% in

EXAMPLE 108 Preparation of2-Amino-5-[4-(2-fluoroethoxy)phenyl]-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) Preparation of Methyl 4-(2-fluoroethoxy)benzoate

Under nitrogen atmosphere to a cold (5° C.) solution of4-hydroxy-benzoic acid methyl ester (7 g, 46 mmol) in DMF (30 ml) wasadded NaH (60%; 2.2 g) portion wise over 20 minutes. After the additionwas completed, the ice bath was removed and the resulting whitesuspension was heated up to room temperature and stirred for 3 hours. Aprepared solution of 1-Bromo-2-fluoro-ethane (6.42 g, 50 56 mmol) in DMF(20 mL) was added and the new mixture was stirred at 50° C. for 18hours. After cooling to room temperature the mixture was poured into amixture of ice and 1 N HCl (1:1) and extracted with ethyl acetate. Theorganic extracts were washed with brine, dried over MgSO₄. Evaporationand purification by flash chromatography (hexane/ethyl acetate 9/1) gavea white solid (7.75. 85% yield); ¹H NMR (400 MHZ, CDCl₃) δ 3.86 (s, 3H),4.20 (m, 1H), 4.21 (m, 1H), 4.27 (m, 1H), 4.28 (m, 1H), 6.93 (d, 2H),7.98 (d, 2H); MS m/e (M+H)⁺ 198; mp 77° C.

Step b) Preparation of 4-(2-Fluoroethoxy)benzoic acid

To a solution of methyl 4-(2-fluoroethoxy)benzoate (7.7 g, 38.85 mmol)in dioxane (100 mL) was added LiOH (2M, 39 mL). The reaction mixture wasstirred at room temperature for 18 hours, and then concentrated invacuo. The residue was dissolved in H₂O (30 ml) and extracted withether. Under cooling the aqueous was acidified with HCl (6N) andextracted with CHCl₃. The organic extracts were dried over MgSO₄.Evaporation and recrystallzation from ethyl acetate and methylenechloride gave the title compound as a white solid (5 g, 71% yield); ¹HNMR (400 MHZ, DMSO-d₆) δ 4.28 (m, 1H), 4.35 (m, 1H,) 4.68 (m, 1H), 4.80(m, 1H), 7.04 (d, 2H), 7.89 (d, 2H); MS m/e (M−H)⁻ 183.1; mp 203° C.

Step c) Preparation of1-(3-bromo-4-fluorophenyl)-2-[4-(2-fluoroethoxy)-phenyl]ethane-1,2-dione

A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran(20 mL, 20 mmol was added at room temperature to a stirred suspension of(3-bromo-4-fluoro-benzyl)triphenylphosphonium bromide (10.6 g, 20 mmol)in tetrahydrofuran (40 mL). The mixture was stirred for 40 minutes, thencooled to −20° C. and treated with 4-(2-fluoroethoxy)benzoyl chloride(4.1 g, 20 mmol) in tetrahydrofuran (40 mL) and stirred for anadditional 2 hours while slowly warming to room temperatute. The mixturewas treated with water (20 mL) and sodium periodate (4.3 g, 20 mmol)then stirred at 50° C. for 18 hours. After cooling to room temperaturethe mixture was extracted with ethyl acetate. The organic extracts werewashed with brine, dried over MgSO₄. Evaporation and purification byflash chromatography (hexane/ethyl acetate 9/1) gave a yellow solid (3g, 41% yield); ¹H NMR (400 MHZ, CDCl₃) δ 4.25 (m, 1H), 4.32 (m, 1H,)4.70 (m, 1H), 4.82 (m, 1H), 7.01 (d, 2H), 7.23 (m, 1H), 7.94 (m, 3H),8.22 (m, 1H); MS m/e (M+CH₃COO)⁻ 427; mp 107° C.

Step d) Preparation of2-Amino-5-[4-(2-fluoroethoxy)phenyl]-5-[4-fluoro-3-(2-fluoropyri-din-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Examples 39 and 40 andemploying methylaminoguanidine and 2-fluoropyridine-3-boronic acid,respectively, the title product was obtained as a white solid, mp 135°C., ¹H NMR (400 MHZ, DMSO-d₆) δ2.93(s, 3H), 4.09 (m, 1H), 4.11 (m, 1H,)4.59 (m, 1H), 4.61 (m, 1H), 6.84, (bs, 2H), 6.86 (m, 2H), 7.30 (m, 3H),7.44 (m,1H), 7.52 (m, 2H), 7.95 (m, 1H), 8.26 (m, 1H); MS m/e (M−H)⁻439.2;

EXAMPLES 109-124 Preparation of2-Amino-5-alkoxyphenyl-5-(3-heteroaryl)phenyl-3-methyl-3,5-dihydro-4H-imidazol-4-oneCompounds

Using essentially the same procedure described in Example 108 andemploying the appropriate boronic acid and 5-(3-bromopheny)hydantoinsubstrate, the compounds shown on Table III were obtained and identifiedby NMR and mass spectral analyses. TABLE III

Ex. mp No R₄ R R₇ R₈ R₉ X ° C. 109 H CH₂CH₂F 4-F H H N 123 110 H CH₂CH₂FH H H CF — 111 H CH₂CH₂F H 6-F H CH 100 112 3-CH₃ CH₂CH₂F 4-F H F CH105-106 113 3-CH₃ CH₂CH₂F 4-F H H N 108-110 114 3-CH₃ CH₂C₆H₅ H H H N107-109 115 3-CH₃ H H H H N 168-170 116 3-CH₃ CH₂CH₂F H H H N 108-110117 3-CH₃ CH₂CN H H H N 220-222 118 3-CH₃ i-propyl H H H N 101-103 1193-CH₃ CH₂CO₂C₂H₅ H H H N 105-107 120 3-CH₃ C₂H₅ H H H N 106-108 1213-CH₃ n-propyl H H H N 102-104 122 3-CH₃ i-butyl H H H N 103-105 1233-CH₃ CH₂CH₂cyclohexyl H H H N 107-109 124 3-CH₃ n-C₃H₆—OC₆H₅ H H H N72-74

EXAMPLE 125 Preparation of2-Amino-5-(3-bromo-4-fluorophenyl)-3-(2-fluoroethyl)-5-(4-trifluoromethoxy-phenyl)-3,5-dihydro-imidazol-4-one

To a stirred mixture of 2-fluoroethylamine hydrochloride (1.50 g; 15.1mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (1.77 g; 12.1 mmol)in DMF was added diisopropylethylamine (3.58 g; 27.7 mmol). The mixturewas stirred under nitrogen atmosphere for 3 hours. Diethyl ether wasadded (35 mL) and the mixture was shaken and the oily product wasallowed to settle to the bottom of the flask, whereupon the ether wasdecanted. This was repeated and the clear oil was dried under highvacuum at ambient temperature for 24 hours. TheN-(2-fluoroethyl)-guanidine product was used without furtherpurification (1.6 g).

A solution of1-(3-bromo-4-fluoro-phenyl)-2-(4-trifluoromethoxy-phenyl)-ethane-1,2-dione(0.181 g; 0.46 mmol) and N-(2-fluoroethyl)-guanidine (0.105 g; 0.74mmol) in a mixture of dioxane, water and ethanol, was treated with solidsodium carbonate heated at 90° C. for five hours, and evaporated todryness. The resultant residue is dissolved in chloroform, washed withwater, dried over sodium sulfate, and evaporated to give the titlecompound as a light-green solid, 116 mg (52% yield), MS (API-ES) 480.3[M+H]+.

EXAMPLES 126-128 Preparation of2-Amino-3-substituted-5-(3-heteroaryl)phenyl-5-(4-trifluoromethoxy-phenyl)-3,5-dihydro-imidazol-4-oneCompounds

Using essentially the same procedure described in Example 108 andemploying the appropriate boronic acid and3-alkyl-2-amino-5-(3-bromopheny)hydantoin substrate, the compounds shownon Table IV were obtained and identified by NMR and mass spectralanalyses. TABLE IV

Ex. mp No R R3 R8 R9 X ° C. 126 CF₃ CH₂CH₂F H H N 166-170 127 CF₃CH₂CH₂F H F CH 138-150 128 CHF₂ C₂H₅ H H C—F

EXAMPLE 129 Preparation of3-Methyl-5-(3-methyl-4-ropoxyphenyl)-2-(propylamino)-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one

A solution of2-amino-5-(4-hydroxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one(74.6 mg, 0.2 mmol) in N,N-dimethylformamide was treated with2-iodopropane (31.2 mg, 0.4 mmol) and Cs₂CO₃ (130 mg, 0.4 mmol) at roomtemperature, stirred overnight at room temperature and quenched withH₂O. The phases were separated, the aqueous phase was extracted withethyl acetate. The organic phase was combined with the extracts, washedsequentially with H₂O and brine, dried over MgSO₄ and evaporated todryness. The resultant residue was purified by flash chromatography withethyl acetate/ethanol (2M ammonia) (90/10) as eluent to afford the titlecompound as a white solid, 60 mg (65% yield), mp 64-66° C.; MS (+) ES:458 (M+H)⁺.

EXAMPLE 130 Preparation of4-iodo-2-methyl-1-[(1R)-1-phenylethoxy]benzene

A cooled solution of PPh₃ (262 mg 10 mmol) in THF was treated withdiethyl azodicarboxylate (1.74 g, 10 mmol) at 0° C., stirred for 5 min,allowed to warm-up to room temperature, treated with4-iodo-2-methylphenol (1.17 g, 5 mmol) and R(+)-1-phenylethanol (1.22 g,10 mmol), stirred for 24 h at room temperature and concentrated invacuo. The resultant residue was purified by flash chromatography(silica gel, 100% hexane) to afford the title compound as a clear oil2.5 g (50%). MS (+): EI 338 M⁺.

EXAMPLE 131 Preparation of2-amino-3-methyl-5-{3-methyl-4-[(1R)-1-phenylethoxy]phenyl{-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one

A solution of 4-iodo-2-methyl-1-[(1R)-1-phenylethoxy]benzene (10 mmol)in triethylamine is treated with tetrakis(triphenylphosphine)Pd (0.69mmol), copper iodide (0.97 mmol) and a solution of3-(primidin-5-yl)ethynlybenzene (10 mmol) in acetonitrile at roomtemperature. The reaction mixture is heated for 1 h at 80° C., cooledand concentrated in vacuo. The resultant residue is purified bychromotography to give5-[3-({3-methyl-4-[(1R)-1-phenyl}ethynyl)phenyl]pyrimidine as an oil, MS(+) ES: 391 (M+H)⁺. A solution of5-[3-({3-methyl-4-[(1R)-1-phenyl}ethynyl)phenyl]pyrimidine (8.3 mmol) inacetone is treated with a warm (˜40° C.) solution of NaHCO₃ (4.98 mmol)and MgSO₄ (12.45 mmol) in water (80 mmol) followed by a single portionof solid KMnO₄ (8.3 mmol), stirred for 40 min. at room temperature andextracted with 1:1 ether:hexane. The extracts are combined, dried overMgSO₄ and concentrated to dryness to give1-{3-methyl-4-[(1R)-1-phenylethoxy]phenyl}-2-(3-pyrimidin-5-ylphenyl)ethane-1,2-dioneas a foam, MS (+) ES: 423 (M+H)⁺. A solution of1-{3-methyl-4-[(1R)-1-phenylethoxy]phenyl}-2-(3-pyrimidin-5-ylphenyl)ethane-1,2-dione(5.0 mmol) in ethanol is treated with N-methylguanidine hydrochloride(5.5 mmol) and an aqueous solution of Na₂CO₃ (10.0 mmol), heated atreflux temperature for 1 h and concentrated in vacuo. The resultantresidue is purified by chromatography to afford the title product as awhite solid, mp 112-114° C. MS (+) ES: 478 (M+H)⁺.

EXAMPLE 132 Preparation of(5R)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one

A racemic mixture of2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-onewas separated by chiral HPLC using Chiralcel AD, 2×25 cm (column) withmobile phase 9% EtOH in hexanes (0.1% diethtylamine) to give the titleR-isomer: [α]₂₅=−13.4 (1% in MeOH); ¹H NMR (DMSOd₆ 300 MHz) δ 2.95 (s,3H), 6.65 (brs, 2H), 7.28 (d, 2H), 7.4-7.45 (m, 3H), 7.5 (m, 1H), 7.55(d, 2H), 7.65 (d, 1H), 7.95-8.0 (m, 1H), 8.2 (m, 1H); MS m/e (M+H)⁺ 445.

EXAMPLE 133 Preparation of(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral HPLC: Chiralcel AD, 2×25 cm (column) with mobilephase 9% EtOH in hexanes/TFA to give the the title product A,[α]₂₅=+11.4 (1% in MeOH);¹H NMR (DMSOd₆ 300 MHz) δ 3.12 (s, 3H), 7.25(m, 3H), 7.4-7.5 (m, 4H), 7.5 (m, 2H), 8.0 (m, 1H), 8.6 (m, 1H), 9.5-9.7(br, 2H); MS m/e (M+H)⁺ 445 and the title product B, [α]₂₅=−10.4 (1% inMeOH); ¹H NMR (DMSOd₆ 300 MHz) δ 3.12 (s, 3H), 7.25 (m, 3H), 7.4-7.5 (m,4H), 7.5 (m, 2H), 8.0 (m, 1H), 8.6 (m, 1H), 9.5-9.7 (br, 2H); MS m/e(M+H)⁺ 445.

EXAMPLE 134 Preparation of(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(6-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(6-fluoropyridin-3-yl)phenyl]-3-methyl-3,5dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(6-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral HPLC: Chiralcel OJ, 0.46×10 cm (column) withmobile phase 15% EtOH in hexanes to give the title S-isomer (A):[α]₂₅=+6 (1% in MeOH); ¹H NMR (DMSOd₆ 300 MHz) δ 2.94 (s, 3H), 6.8 (brs,2H), 7.08 (d, 2H), 7.12 (t, 1H), 7.28 (m, 2H), 7.4-7.5 (m, 3H), 7.6 (dd,1H), 8.05 (m, 1H), 8.3 (s, 1H); MS m/e (M+H)⁺ 445 and the title R-isomer(B): [α]₂₅=−7.4 (1% in MeOH); ¹H NMR (DMSOd₆ 300 MHz) δ 2.94 (s, 3H),6.8 (brs, 2H), 7.08 (d, 2H), 7.12 (t, 1H), 7.28 (m, 2H), 7.45 (d, 2H),7.4-7.5 (m, 1H), 7.6 (dd, 1H), 8.05 (m, 1H), 8.3 (s, 1H); MS m/e (M+H)⁺445.

EXAMPLE 135 Preparation of(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(6-fluoropyridin-3-yl)phenyl-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(6-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(6-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral HPLC: Chiralcel OJ, 0.46×10 cm (column) withmobile phase 15% EtOH in hexanes to give the title S-isomer (A):[α]₂₅=−7.4 (1% in MeOH); ¹H NMR (DMSOd₆ 300 MHz) δ 2.95 (s, 3H), 6.7(brs, 2H), 7.08 (d, 2H), 7.12 (t, 1H), 7.25 (dd, 1H), 7.4 (t, 1H),7.5-7.55 (m, 4H), 7.7 (s, 1H), 8.2 (m, 1H), 8.37 (s, 1H); MS m/e (M+H)⁺427; and the title R-isomer (B): [α]₂₅=+8.4(1% in MeOH); ¹H NMR (DMSOd₆300 MHz) δ 2.95 (s, 3H), 6.7 (brs, 2H), 7.08 (d, 2H), 7.12 (t, 1H), 7.25(dd, 1H), 7.4 (t, 1H), 7.5-7.55 (m, 4H), 7.7 (s, 1H), 8.2 (m, 1H), 8.37(s, 1H); MS m/e (M+H)⁺ 427.

EXAMPLE 136 Preparation of(5S)-2-Amino-5-(3,4-diethoxyphenyl)-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-(3,4-diethoxyphenyl)-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-amino-5-(3,4-diethoxyphenyl)-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated using a WhelkO, 2×25 cm chiral HPLC column and 20% EtOH inheptane with 1% triethylamine, as the eluent to give the title S-isomer(A) as a white solid, [α]₂₅=−22.2, 1% in methanol; ¹H NMR (DMSOd₆ 300MHz) δ 1.3 (t, 6H), 2.9 (s, 3H), 3.9 (dxq, 4H), 6.6 (b, 2H), 6.8 (d, 1H)7.0 (m, 2H), 7.3 (t, 1H), 7.5 (m, 3H), 7.9 (s, 1H), 8.3 (m, 1H); MS m/e(M)⁺ 467; and the title R-isomer (B) as a white solid, [α]₂₅=+26.0, 1%in methanol; ¹H NMR (DMSOd₆ 300 MHz) δ 1.3 (t, 6H), 2.9 (s, 3H), 3.9(dxq, 4H), 6.6 (b, 2H), 6.8 (d, 1H) 7.0 (m, 2H), 7.3 (t, 1H), 7.5 (m,3H), 7.9 (s, 1H), 8.3 (m, 1H); MS m/e (M)⁺ 467.

EXAMPLE 137 Preparation of(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2.5-difluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl-5-[3-(2,5-difluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2,5-difluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral HPLC: Chiralcel OJ, 2×25 cm (column) with mobilephase 35% EtOH in hexanes/DEA to give the title S-isomer (A): [α]₂₅=+2.8(1% in MeOH); ¹H NMR (DMSOd₆ 300 MHz) δ 2.94 (s, 3H), 6.7 (brs, 2H),7.08 (d, 2H), 7.12 (t, 1H), 7.4-7.5 (m, 5H), 7.7 (s, 1H), 8.0 (m, 1H),8.2 (m, 1H); MS m/e (M+H)⁺ 445; and the title R-isomer (B):[α]₂₅=+2.8(1% in MeOH); ¹H NMR (DMSOd₆ 300 MHz) δ 2.94 (s, 3H), 6.7(brs, 2H), 7.08 (d, 2H), 7.12 (t, 1H), 7.4-7.5 (m, 5H), 7.7 (s, 1H), 8.0(m, 1H), 8.2 (m, 1H); MS m/e (M+H)⁺ 445.

EXAMPLE 138 Preparation of(5S)-2-Amino-5-[4-(2-fluoroethoxy)-3-methylphenyl]-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-[4-(2-fluoroethoxy)-3-methylphenyl]-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3.5-dihydro-4H-imidazol-4-one[B]

Using essentially the same procedure described in Examples 133-137 andemploying a racemic mixture of2-amino-5-[4-(2-fluoroethoxy)-3-methylphenyl]-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one,the title S-isomer (A) was obtained as a white solid, mp 116-118° C.;[α]₂₅=−31.46 (1% in DMSO); MS(+)ES: 438 (M+H)⁺; and the title R-isomerwas obtained as a white solid, mp 112-114° C.; [α]₂₅=+35 (1% in DMSO);MS(+)ES: 438 (M+H)⁺.

EXAMPLE 139 Preparation of(5S)-2-Amino-5-[4-(2-fluoroethoxy)phenyl]-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-[4-(2-fluoroethoxy)phenyl]-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-amino-5-[4-(2-fluoroethoxy)phenyl]-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral HPLC: Chiralcel AD, 2×25 cm using mobile phaseEtOH:Hexane (15:85) and a flow rate of 20 mL/min to give the titleS-isomer (A) as a white solid, mp 120° C.; [α]₂₅=−35.09 (0.53% in MeOH);¹H NMR (400 MHZ, DMSO-d₆) δ 2.97 (s, 3H), 4.14-4.15 (m, 1H), 4.20-4.21(m, 1H,) 4.65-4.66 (m, 1H), 4.74-4.75 (m, 1H), 6.67 (bs, 2H), 6.88-6.89(d, 2H), 7.34 (m, 1H), 7.35-7.37 (d, 2H), 7.57, (m, 1H), 7.65 (m, 1H),8.92 (s, 2H), 9.22 (s, 1H); MS m/e (M−H)⁻ 422.1; and the title R-isomeras a white solid, mp 120° C.; [α]₂₅=+31.2 (1% in MeOH); ₁H NMR (400 MHZ,DMSO-d₆) δ 2.97 (s, 3H), 4.15-4.16 (m, 1H), 4.20-4.21 (m, 1H), 4.65-4.66(m, 1H), 4.74-4.75 (m, 1H), 6.67 (bs, 2H), 6.88-6.89 (d, 2H), 7.34 (m,1H), 7.35-7.37 (d, 2H), 7.55, (m, 1H), 7.65 (m, 1H), 8.92 (s, 2H), 9.22(s, 1H); MS m/e (M−H)⁻ 422.1.

EXAMPLES 140 AND 141 Preparation of(5S)-2-Amino-5-[4-(2-fluoroethoxy)phenyl]-3-methyl-5-(3-heteroarylphenyl)-3,5-dihydro-4H-imidazol-4-oneCompounds

Using essentially the same procedure described in Example 40 andemploying(5S)-2-amino-5-(3-bromophenyl)-5-[4-(2-fluoroethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-oneand a suitable heteroarylboronic acid, the compounds shown on Table Vwere obtained and identified by HNMR and mass spectral analyses. TABLE V

Ex. mp No R9 X [α]₂₅ ° C. 140 H N −18.4 (1% MeOH) 145 141 F CH — 106

EXAMPLE 142 Preparation of(5S)-2-Amino-5-[4-fluoro-3-(5-fluoropyridin-3-yl)phenyl]-5-(4-methoxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-[4-fluoro-3-(5-fluoropyridin-3-yl)phenyl]-5-(4-methoxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-amino-5-[4-fluoro-3-(5-fluoropyridin-3-yl)phenyl]-5-(4-methoxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral HPLC: Chiralcel OJ, 2×25 cm (column) with mobilephase 30% EtOH in hexanes (0.1% diethtylamine) to give the titleS-isomer (A): [α]₂₅=−37.6 (1% in MeOH); ¹H NMR (DMSOd₆ 300 MHz) δ 2.93(s 3H), 3.63 (s 3H), 6.6 (brs, 2H), 6.8 (d, 2H), 7.22-7.35 (m, 3H), 7.5(m, 1H), 7.6 (dd, 1H), 7.8 (m, 1H), 8.5 (d, 1H), 8.6 (d, 1H); MS m/e(M+H)⁺ 409 and the title R-isomer (B): [α]₂₅=+35.4 (1% in MeOH); ¹H NMR(DMSOd₆ 300 MHz) δ 2.93 (s 3H), 3.63 (s 3H), 6.6 (brs, 2H), 6.8 (d, 2H),7.22-7.35 (m, 3H), 7.5 (m, 1H), 7.6 (dd, 1H), 7.8 (m, 1H), 8.5 (d, 1H),8.6 (d, 1H); MS m/e (M+H)⁺ 409.

EXAMPLE 143 Preparation of(5S)-2-Amino-5-[4-fluoro-3-(4-fluoropyridin-3-yl)phenyl]-5-(4-methoxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-[4-fluoro-3-(4-fluoropyridin-3-yl)phenyl]-5-(4-methoxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-amino-5-[4-fluoro-3-(4-fluoropyridin-3-yl)phenyl]-5-(4-methoxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral HPLC: Chiralcel OJ, 0.46×25 cm (column) withmobile phase 80% EtOH in hexanes (0.1% diethtylamine) to give the titleS-isomer (A): [α]₂₅=−40 (1% in MeOH); ¹H NMR (DMSOd₆ 300 MHz) δ 2.93 (s,3H), 3.66 (s, 3H), 6.65 (brs, 2H), 6.8 (d, 2H), 7.3 (m, 3H), 7.43 (m,1H), 7.52 (m, 2H), 8.55 (d, 1H), 8.63 (t, 1H); MS m/e (M+H)⁺ 409; andtitle R-isomer (B): [α]₂₅=+38.8 (1% in MeOH); ¹H NMR (DMSOd₆ 300 MHz) □2.93 (s, 3H), 3.66 (s, 3H), 6.65 (brs, 2H), 6.8 (d, 2H), 7.3 (m, 3H),7.43 (m, 1H), 7.52 (m, 2H), 8.55 (d, 1H), 8.63 (t, 1H), MS m/e (M+H)⁺409.

EXAMPLE 144 Preparation of4-[4-Fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-4-(4-trifluoromethoxyphenyl)-4,5-dihydro-1H-imidazol-2-ylamine

Step a) Preparation of Compound 2

A mixture of 1 (2.00 g, 5.1 mmol) and 1-methyl-2-thiourea (2.07 g, 23.0mmol) in ethanol (50 mL) and dioxane (50 mL) was stirred at roomtemperature for 5 min. A solution of sodium carbonate (2.44 g, 23.0mmol) in water (20 mL) was added and the reaction was stirred at 85° C.for 15 min. The reaction was then cooled to room temperature,concentrated and diluted with ethyl acetate (100 mL) and brine (20 mL).The organic layer was separated and washed with brine (10 mL), driedover sodium sulfate, filtered and concentrated. Purification by flashchromatography (silica, 1:9 ethyl acetate/hexanes) afforded 2 (2.30 g,97%) as a yellow solid: ¹H NMR (300 MHz, CD₃OD) δ 7.61 (dd, J=6.3, 2.4Hz, 1H), 7.46-7.27 (m, 6H), 3.27 (s, 3H).

Step b) Preparation of Compound 3

A mixture of 2 (2.20 g, 4.75 mmol) and 1.0 M borane tetrahydrofurancomplex in tetrahydrofuran (47.5 mL, 47.5 mmol) in tetrahydrofuran (66mL) was heated at reflux overnight, then treated with 6 N HCl (24 mL,143 mmol) and heated at 80° C. for 1 h. The reaction was cooled to roomtemperature, neutralized with sodium bicarbonate solid (12.0 g, 143mmol) and diluted with ethyl acetate (200 mL). The organic layer wasseparated and washed with brine (20 mL), dried over sodium sulfate,filtered and concentrated. Purification by flash chromatography (silica,1:9 to 2:8 ethyl acetate/hexanes) afforded 3 (0.73 g, 34%) as acolorless oil: ¹H NMR (300 MHz, CDCl₃) δ 8.14 (s, 1H), 7.42 (m, 1H),7.31-7.05 (m, 6H), 4.18 (s, 2H), 3.19 (s, 3H); ESI MS m/z 450[C₁₇H₁₃BrF₄N₂OS+H]⁺.

Step c) Preparation of Compound 4

A mixture of 3 (0.73 g, 1.63 mmol), methyl iodide (0.25 g, 1.79 mmol) inisopropanol (10 mL) was heated at 80° C. for 1 h, concentrated,redissolved in isopropanol (20 mL), cooled to 0° C. and charged withammonia gas (2.0 g). The reaction vessel was sealed and heated at 80° C.for 48 h. The reaction was cooled to room temperature, concentrated andpurified by flask chromatography (100:0:0 to 80:20:0.5 methylenechloride/methanol/concentrated ammonium hydroxide) afforded 4 (0.62 g,88%) as a colorless syrup: ¹H NMR (300 MHz, CD₃OD) δ 7.62 (dd, J=6.3,2.4 Hz, 1H), 7.61-7.20 (m, 6H), 4.35 (s, 2H), 3.08 (s, 3H); ESI MS m/z432 [C₁₇H₁₄BrF₄N₃O+H]⁺.

Step d) Preparation of Compound 5

A mixture of 4 (0.52 g, 1.20 mmol), 4-dimethylaminopyridine (0.77 g,6.32 mmol) and di-tert-butyldicarbonate (1.38 g, 6.32 mmol) intetrahydrofuran (5 mL) was stirred at room temperature for 1 h andconcentrated. Purification by flash chromatography (silica, 1:9 to 2:8ethyl acetate/hexanes) afforded 5 (0.49 g, 65%) as a white solid: ¹H NMR(300 MHz, CD₃OD) δ 7.67 (dd, J=6.6, 2.1 Hz, 1H), 7.44-7.03 (m, 6H), 4.05(d, J=9.9 Hz, 1H), 3.86 (d, J=9.9 Hz, 1H), 2.79 (s, 3H), 1.39 (s, 18H);ESI MS m/z 632 [C₂₇H30BrF₄N₃O₅+H]⁺.

Step e) Preparation of Compound 6

A mixture of 5 (0.19 g, 0.300 mmol), 2-fluoropyridine-3-boronic acid(0.064 g, 0.451 mmol), sodium carbonate (0.096 g, 0.900 mmol),bis(triphenylphosphino)palladium (II) dichloride (0.021 g, 0.030 mmol)and triphenylphosphine (0.016 g, 0.060 mmol) in 1:1 toluene/EtOH (10 mL)was degassed and heated at 110° C. for 20 min. The mixture was cooled toroom temperature and concentrated. Purification by flash chromatography(silica, 1:9 to 4:6 ethyl acetate/hexanes) afforded 6 (0.055 g, 28%) asa white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.24 (m, 1H), 7.82 (m, 1H),7.48-7.11 (m, 8H), 4.03 (d, J=9.5 Hz, 1H), 3.95 (d, J=9.5 Hz, 1H), 2.78(s, 3H), 1.31 (s, 18H); ESI MS m/z 649 [C₃₂H₃₃F₅N₄O₅+H]⁺.

Step f) Preparation of4-[4-fluoro-3-(2-fluoro-pyridin-3-yl)-phenyl]-1-methyl-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-1H-imidazol-2-ylamine

A mixture of 6 (0.055 g, 0.085 mmol) and 4 M hydrogen chloride indioxane (5 mL) was heated at 50° C. for 1 h, cooled to room temperatureand concentrated. The reaction mixture was then diluted with chloroform(50 mL) and sodium bicarbonate (10 mL). The organic layer was separatedand washed with brine (20 mL), dried over sodium sulfate, filtered andconcentrated. Purification by preparative HPLC afforded the titleproduct as a white solid, 0.031 g (82% yield), mp 65-70° C.; ¹H NMR (500MHz, CD₃OD) δ 8.22 (m, 1H), 7.95 (m, 1H), 7.35-7.23 (m, 8H), 4.10 (t,J=7.5 Hz, 2H), 2.93 (t, J=7.5 Hz, 3H); IR (ATR) 3059, 2926, 1670, 1641,1570, 1503, 1427, 1253, 1201, 1161, 829, 804, 765, 718 cm⁻¹; ESI MS m/z449 [C₂₂H₁₇F₅N₄O+H]⁺.

EXAMPLE 145 Preparation of2-Amino-5-[3-(2-fluoro-pyridin-3-yl)-phenyl]-3-methyl-5-(4-trifluoromethoxy-phenyl)-3,5-dihydro-imidazole-4-thione

Step a) Preparation of Compound 2

A mixture of methylamine hydrochloride (0.210 g, 3.18 mmol),triethylamine (0.320 g, 3.18 mmol) and 1 (0.470 g, 1.06 mmol) in ethanolwas stirred at 70° C. for 1 h. The solvents were evaporated and theresidue partitioned between ethyl acetate and water. The organic layerwas separated and washed with brine (30 mL), dried over sodium sulfate,filtered and concentrated to afford 2 (0.460 g, 99%) as a yellow solid:¹H NMR (300 MHz, CDCl₃) δ 7.71 (br s, 1H), 7.58-7.49 (m, 2H), 7.37 (d,J=8.9 Hz, 2H), 7.30-7.19 (m, 3H), 3.68 (s, 3H).

Step b) Preparation of Compound 3

A mixture of 2 (0.458 g,1.05 mmol) and t-butyl hydroperoxide (1.88 g ofa 70% solution in water, 21.0 mmol) in methanol (50 mL) and concentratedaqueous ammonium hydroxide (10 mL) was stirred overnight at roomtemperature. After this time, 10% aqueous sodium thiosulfate (30 mL) wasadded; the mixture was concentrated to remove most of the methanol andthen the aqueous mixture was diluted with methylene chloride. Theorganic layer was separated, washed with brine (30 mL), dried oversodium sulfate, filtered and concentrated. Purification of the resultantresidue by flash chromatography (silica, 95:5 methylenechloride/methanol) afforded 3 (0.250 g, 57%) as a white solid: ¹H NMR(300 MHz, CDCl₃) δ 7.88 (t, J=1.7 Hz, 1H), 7.81 (d, J=8.9 Hz, 2H),7.72-7.65 (m, 2H), 7.36 (t, J=7.8 Hz, 1H), 6.98 (d, J=8.9 Hz, 2H), 3.90(s, 3H); ESI MS m/z 444 [C₁₇H₁₃BrF₃N₃OS+H]⁺.

Step c) Preparation of2-amino-5-[3-(2-fluoro-pyridin-3-yl)-phenyl]-3-methyl-5-(4-trifluoromethoxy-phenyl)-3,5dihydro-imidazole-4-thione

A mixture of 3 (0.16 g, 0.38 mmol), 2-fluoropyridine-3-boronic acid(0.075 g, 0.530 mmol), bis(triphenylphosphino)palladium(II) chloride(0.013 g, 0.019 mmol), triphenylphosphine (0.010 g, 0.038 mmol) andsodium carbonate (0.121 g 1.14 mmol) in 3:1 DME/water (6.0 mL) washeated at 80° C. for 1 h. The mixture was cooled to room temperature andconcentrated in vacuo. The resultant residue was diluted with ethylacetate and water. The organic layer was separated and washed with brine(20 mL), dried over sodium sulfate, filtered and concentrated.Purification of this residue by flash chromatography (silica, 97:2.5:0.5methylene chloride/methanol/concentrated ammonium hydroxide) afforded0.087 g of a pale yellow solid. This material was freeze dried from 1:1acetonitrile/water (6 mL) to afford the title product as a pale yellowsolid, 0.069 g (39% yield), mp 89-99° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.17(dt, J=4.8, 1.5 Hz, 1H), 7.86-7.79 (m, 1H), 7.65 (br s, 1H), 7.55-7.48(m, 4H), 7.44-7.38 (m, 1H), 7.27-7.25 (m, 1H), 7.14 (d, J=8.9 Hz, 2H),3.48 (s, 3H); ESI MS m/z 461 [C₂₂H₁₆F₄N₄OS+H]⁺;

EXAMPLE 146

Evaluation of the Inhibition of hBACE1, MuBACE1 and hBACE2 by TestCompounds

Assay Conditions: 10 nM human BACE1 (or 10 nM Murine BACE1, 1.5 nM humanBACE2) 25 μM substrate (WABC-6, MW 1549.6, from AnaSpec); final bufferconditions: 50 mM Na-Acetate, pH 4.5, 0.05% CHAPS, 25% PBS; temperature:room temperature; reagent information:Na-Acetate: Aldrich, Cat.#24,124-5 CHAPS: Research Organics, Cat. # 1304C 1× PBS: Mediatech(Cellgro), Cat# 21-031-CV; peptide substrate AbzSEVNLDAEFRDpa: AnaSpec,Peptide Name: WABC-6; determination of stock substrate(AbzSEVNLDAEFRDpa) concentration: a 25 mM stock solution in dimethylsulfoxide (DMSO) is prepared using the peptide weight and MW and dilutedto 25 μM. The concentration is determined by absorbance at 354 nm usingan extinction coefficient ε of 18172 M⁻¹cm⁻¹, The substrate stock isstored in small aliquots at −80° C. [Substrate Stock]=ABS^(354 nm)*10⁶/18172 (in mM)

Determination of Stock Enzyme Concentration: The stock concentration ofeach enzyme by ABS at 280 nm using □ of 64150 M⁻¹cm⁻¹ for hBACE1 andMuBACE1, 62870 M⁻¹cm⁻¹ for hBACE2 in 6 M Guanidinium Hydrochloride (fromResearch Organics, Cat. # 5134G-2), pH 6.

(The extinction coefficient ε^(280 nm) for each enzyme was calculatedbased on known amino acid composition and published extinctioncoefficients for Trp (5.69 M⁻¹ cm⁻¹) and Tyr (1.28 M⁻¹ cm⁻¹) residues(Anal. Biochem. 182, 319-326).

Dilution and mixinq steps: total reaction volume: 100 μL

-   1. 2× inhibitor dilutions in buffer A(66.7 mM Na-Acetate, pH 4.5,    0.0667% CHAPS) are prepared,-   2. 4× enzyme dilution in buffer A(66.7 mM Na-Acetate, pH 4.5,    0.0667% CHAPS) are prepared,-   3. 100 μM substrate dilution in 1× PBS is prepared,-   4. 50 μL 2× Inhibitor and 25 μL 100 μM substrate are added to each    well of 96-well plate (from DYNEX Technologies, VWR #: 11311-046),    the immediately 25 μL 4× enzyme are added to the inhibitor and    substrate mixer, the fluorescence readings are initiated.

Fluorescence Readings: Readings at λ_(ex) 320 nm and λ_(em) 420 nm aretaken every 40-sec for 30 min at room temperature to determine thelinear slope for substrate cleavage rate (v_(i)).

Calculation of % Inhibition: % Inhibition=100*(1−v_(i)/v₀)

-   (v_(i=)substrate cleavage rate in the presence of inhibitor,-   v₀₌substrate cleavage rate in the absence of inhibitor)-   IC₅₀ Determination: % Inhibition=[(B*IC₅₀ ^(n))+(100*I₀ ^(n))]/(IC₅₀    ^(n)+I₀ ^(n)),    Fluorescent Kinetic Assay for Human Recombinant BACE 2

This assay is used to provide kinetic and selectivity parameters for theanalyses of the tested compounds.

Materials and methods: final assay conditions: 10 nM human BACE1 (or 10nM Murine BACE1, 1.5 nM human BACE2) 25 μM Substrate (WABC-6, MW 1549.6,from AnaSpec). Final buffer conditions: 50 mM Na-Acetate, pH 4.5, 0.05%CHAPS, 25% PBS. Temperature: room temperature. Reagent Information:Na-Acetate: Aldrich, Cat.# 24,124-5 CHAPS: Research Organics, Cat. #1304C 1× PBS: Mediatech (Cellgro), Cat# 21-031-CV Peptide SubstrateAbzSEVNLDAEFRDpa: AnaSpec, Peptide Name: WABC-6

Determination of stock substrate (AbzSEVNLDAEFRDpa) concentration: A 25mM stock solution in DMSO is prepared using the peptide weight and MW,and diluted to 25 μM. The concentration is determined by absorbance at354 nm using an extinction coefficient ε of 18172 M⁻¹cm⁻¹. The substratestock is stored in small aliquots at −80° C. [SubstrateStock]=ABS^(354 nm)*10⁶/18172 (in mM)

Determination of stock enzyme concentration: The stock concentration ofeach enzyme is determined by ABS at 280 nm using ε of 64150 M⁻¹cm⁻¹ forhBACE1 and MuBACE1, 62870 M⁻¹cm⁻¹ for hBACE2 in 6 M guanidiniumhydrochloride (from Research Organics, Cat. # 5134G-2), pH 6. (Theextinction coefficient ε^(280 nm) for each enzyme is calculated based onknown amino acid composition and published extinction coefficients forTrp (5.69 M−¹ cm⁻¹) and Tyr (1.28 M⁻¹ cm⁻¹) residues (Anal. Biochem.182, 319-326).)

Dilution and Mixing Steps: Total Reaction Voume.: 100 μL

-   1. 2× inhibitor dilutions in buffer A(66.7 mM Na-Acetate, pH 4.5,    0.0667% CHAPS) are prepared,-   2. 4× enzyme dilution in buffer A(66.7 mM Na-Acetate, pH 4.5,    0.0667% CHAPS) are prepared,-   3. 100 μM substrate dilution in 1× PBS, 50 μL 2× Inhibitor and 25 μL    100 μM substrate are added to each well of 96-well plate (from DYNEX    Technologies, VWR #: 11311-046), then immediately 25 μL 4× enzyme is    added to the inhibitor and substrate mixer and the fluorescence    readings are initiated.

Fluorescence Readings: Readings at λ_(ex) 320 nm, λ_(em) 420 nm aretaken every 40-sec for 30 min at room temperature and to determine thelinear slope for substrate cleavage rate (v_(i)).

Analysis of calculation of % inhibition: % Inhibition=100*(1−v_(i)/v₀)

-   v_(i)=substrate cleavage rate in the presence of inhibitor,-   v₀=substrate cleavage rate in the absence of inhibitor)-   IC₅₀ Determination:-   % Inhibition=((B*IC₅₀ ^(n))+(100*I₀ ^(n)))/(IC₅₀ ^(n)+I₀ ^(n)),

The data obtained are shown on Table VI. TABLE VI Ex. IC₅₀ (μM) No.BACE1 BACE1/BACE2  5 B III  6 B III  7 A II  8 A II  9 A II 10 A II 11 AII 12 A II 13 A II 14 A II 15 B II 16 A III 17 A III 18 A II 19 A III 20B III 21 A II 22 A III 23 A II 24 A II 25 A II 26 A II 27 A II 28 A II29 A II 30 B III 31 B III 32 A III 36 A III 37 A III  38A C III  38B AII 41 B II 42 B II 43 A II 44 A II 46 B II 47 B II 48 C II 49 B I 50 AII 51 A III 52 B II 53 B III 54 A I 55 A II 56 A I 57 A II 58 A II 59 AII 60 A II 61 A II 62 A II 63 A I 64 C III 65 B II 66 A II 67 A III 68 BIII 69 A III 70 A II 71 A III 72 B II 73 B II 74 A II 75 B II 77 A I 78A II 79 A II 80 A III 81 A II 82 A II 83 A II 84 B I 86 A I 88 A II 89 AII 90 A II 91 A II 92 A II 93 A II 94 B II 95 A II 96 A II 97 A II 99 AIII 100  B III 101A C III 101B A I 102A B III 102B A II 103A C III 103BA II 104  A II 105A B III 105B A II 106A C III 106B A I 107A A I 107B CIII 108  A II 109  A II 110  A II 111  B III 112  A II 113  A I 114  AII 115  A II 116  A II 117  A II 118  A I 119  B II 120  A I 121  A II122  A II 123  B II 124  A II 126  B I 127  B I 128  B II 131  A II 132 C III 133A B III 133B A II 134A B III 134B A II 135A C III 135B A II136A A II 137A C III 137B A II 138A A I 138B C III 139A A I 139B B III140  A I 141  A II 142A C III 142B A II 143A C III 143B A II 144  B I145  A IIFor Table VIA = 0.01 μM-0.10 μMB = 0.11 μM-1.00 μMC = >1.00 μMI = >100-fold selectivityII = 10-100-fold selectivityIII = <10-fold selectivityResults and Discussion:

As can be seen from the data shown on Table VI hereinabove, thecompounds of the invention are potent and selective inhibitors of BACE1.

1. A compound of formula I

wherein W is CO, CS or CH₂; X is N, NO or CR₁₀; Y is N, NO or CR₁₁; Z isN, NO or CR₁₉ with the proviso that no more than two of X, Y or Z may beN or NO; R₁ and R₂ are each independently H, COR₂₀, CO₂R₂₁ or anoptionally substituted C₁-C₄alkyl group; R₃ is H, OR₁₂ or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl oraryl(C₁-C₆)alkyl group each optionally substituted; R₄ and R₅ are eachindependently H, halogen, NO₂, CN, OR₁₃, NR₁₄R₁₅ or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈cycloalkyl group eachoptionally substituted or when attached to adjacent carbon atoms R₄ andR₅ may be taken together with the atoms to which they are attached toform an optionally substituted 5- to 7-membered ring optionallycontaining one or two heteroatoms selected from O, N or S; R₆, R₇, R₈,R₉, R₁₀, R₁₁ and R₁₉ are each independently H, halogen, NO₂, CN, OR₁₆,NR₁₇R₁₈ or a C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl orC₃-C₈cycloalkyl group each optionally substituted; n is 0 or 1;

is a single bond when n is 0 or a double bond when n is 1; R₁₂, R₁₃,R₁₆, R₂₀ and R₂₁ are each independently H or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl or arylgroup each optionally substituted; and R₁₄, R₁₅, R₁₇ and R₁₈ are eachindependently H or C₁-C₄alkyl; or a tautomer thereof, a stereoisomerthereof or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1 wherein W is CO.
 3. The compound according to claim1 wherein R₁ and R₂ are H and R₃ is C₁-C₄ alkyl.
 4. The compoundaccording to claim 1 wherein n is
 1. 5. The compound according to claim1 having the structure Ia


6. The compound according to claim 5 having the structure Ib


7. The compound according to claim 6 wherein R₃ is methyl.
 8. Thecompound according to claim 7 wherein Y is CR₁₁ and R₁ and R₂ are H. 9.The compound according to claim 1 selected from the group consisting of:2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;4-[2-amino-4-(4-methoxy-3-methylphenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-2-pyridin-3-ylbenzonitrile;2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(4-methyl-3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-3-ethyl-5-(4-methoxy-3-methylphenyl)-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-3-methyl-5-(3-pyrimidin-2-ylphenyl)-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-hydroxy-3-methylphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3,4-diethoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3,4-dimethoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-cyclopentyl-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-methoxy-3-propoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-butoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-isopropoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(1,3-benzodioxol-5-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(2,3-dihydro-1-benzofuran-5-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;5-[2-amino-1-methyl-5-oxo-4-(3-pyridin-3-ylphenyl)-4,5-dihydro-1H-imidazol-4-yl]-2-methoxybenzonitrile;2-amino-5-(3-fluoro-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-chloro-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-(3,4,5-trimethoxyphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyridin-4-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-ethoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-[(4-trifluoromethoxy-3-trifluoromethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3,4-diethoxyphenyl)-5-(4-fluoro-3-pyridin-3-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-chloro-4-trifluoromethoxyphenyl)-5-(4-fluoro-3-pyridin-3-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;a tautomer thereof; a stereoisomer thereof; and a pharmaceuticallyacceptable salt thereof.
 10. A method for the treatment, prevention oramelioration of a disease or disorder characterized by elevatedβ-amyloid deposits or β-amyloid levels in a patient which comprisesproviding said patient with a therapeutically effective amount of acompound of formula I

wherein W is CO, CS or CH₂; X is N, NO or CR₁₀; Y is N, NO or CR₁₁; Z isN, NO or CR₁₉ with the proviso that no more than two of X, Y or Z may beN or NO; R₁ and R₂ are each independently H, COR₂₀, CO₂R₂₁ or anoptionally substituted C₁-C₄alkyl group; R₃ is H, OR₁₂ or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl oraryl(C₁-C₆)alkyl group each optionally substituted; R₄ and R₅ are eachindependently H, halogen, NO₂, CN, OR₁₃, NR₁₄R₁₅ or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈cycloalkyl group eachoptionally substituted or when attached to adjacent carbon atoms R₄ andR₅ may be taken together with the atoms to which they are attached toform an optionally substituted 5- to 7-membered ring optionallycontaining one or two heteroatoms selected from O, N or S; R₆, R₇, R₈,R₉, R₁₀, R₁₁ and R₁₉ are each independently H, halogen, NO₂, CN, OR₁₆,NR₁₇R₁₈ or a C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl orC₃-C₈cycloalkyl group each optionally substituted; n is 0 or 1;

is a single bond when n is 0 or a double bond when n is 1; R₁₂, R₁₃,R₁₆, R₂₀ and R₂₁ are each independently H or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl or arylgroup each optionally substituted; and R₁₄, R₁₅, R₁₇ and R₁₈ are eachindependently H or C₁-C₄alkyl; or a tautomer thereof, a stereoisomerthereof or a pharmaceutically acceptable salt thereof.
 11. The methodaccording to claim 10 having a formula I compound wherein the structureis


12. The method according to claim 11 having a formula I compound whereinthe structure is


13. The method according to claim 12 wherein said disease or disorder isselected from the group consisting of Alzheimer's disease; mildcognitive impairment; Down's syndrome; hereditary cerebral hemorrhagewith amyloidosis of the Dutch type; cerebral amyloid angiopathy; anddegenerative dementia.
 14. The method according to claim 13 wherein saiddisease is Alzheimer's disease.
 15. A pharmaceutical composition whichcomprises a pharmaceutically acceptable carrier and an effective amountof a compound of formula I

wherein W is CO, CS or CH₂; X is N, NO or CR₁₀; Y is N, NO or CR₁₁; Z isN, NO or CR₁₉ with the proviso that no more than two of X, Y or Z may beN or NO; R₁ and R₂ are each independently H, COR₂₀, CO₂R₂₁ or anoptionally substituted C₁-C₄alkyl group; R₃ is H, OR₁₂ or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl oraryl(C₁-C₆)alkyl group each optionally substituted; R₄ and R₅ are eachindependently H, halogen, NO₂, CN, OR₁₃, NR₁₄R₁₅ or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈cycloalkyl group eachoptionally substituted or when attached to adjacent carbon atoms R₄ andR₅ may be taken together with the atoms to which they are attached toform an optionally substituted 5- to 7-membered ring optionallycontaining one or two heteroatoms selected from O, N or S; R₆, R₇, R₈,R₉, R₁₀, R₁₁ and R₁₉ are each independently H, halogen, NO₂, CN, OR₁₆,NR₁₇R₁₈ or a C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl orC₃-C₈cycloalkyl group each optionally substituted; n is 0 or 1;

is a single bond when n is 0 or a double bond when n is 1; R₁₂, R₁₃,R₁₆, R₂₀ and R₂₁ are each independently H or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl or arylgroup each optionally substituted; and R₁₄, R₁₅, R₁₇ and R₁₈ are eachindependently H or C₁-C₄alkyl; or a tautomer thereof, a stereoisomerthereof or a pharmaceutically acceptable salt thereof.
 16. Thecomposition according to claim 15 having a formula I compound whereinthe structure is Ia


17. The composition according to claim 16 having a formula I compoundwherein the structure is Ib


18. The composition according to claim 17 wherein R₁ and R₂ are H; R₃ ismethyl; and Y is CR₁₁.
 19. The composition according to claim 15 havinga formula I compound selected from the group consisting of:2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;4-[2-amino-4-(4-methoxy-3-methylphenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-2-pyridin-3-ylbenzonitrile;2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(4-methyl-3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-3-ethyl-5-(4-methoxy-3-methylphenyl)-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-3-methyl-5-(3-pyrimidin-2-ylphenyl)-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-hydroxy-3-methylphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3,4-diethoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3,4-dimethoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-cyclopentyl-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-methoxy-3-propoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-butoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-isopropoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(1,3-benzodioxol-5-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(2,3-dihydro-1-benzofuran-5-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;5-[2-amino-1-methyl-5-oxo-4-(3-pyridin-3-ylphenyl)-4,5-dihydro-1H-imidazol-4-yl]-2-methoxybenzonitrile;2-amino-5-(3-fluoro-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-chloro-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-(3,4,5-trimethoxyphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyridin-4-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-ethoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-[(4-trifluoromethoxy-3-trifluoromethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3,4-diethoxyphenyl)-5-(4-fluoro-3-pyridin-3-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-chloro-4-trifluoromethoxyphenyl)-5-(4-fluoro-3-pyridin-3-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;a tautomer thereof; a stereoisomer thereof; and a pharmaceuticallyacceptable salt thereof.
 20. A process for the preparation of a compoundof formula I

wherein W is CO, CS or CH₂; X is N, NO or CR₁₀; Y is N, NO or CR₁₁; Z isN, NO or CR₁₉ with the proviso that no more than two of X, Y or Z may beN or NO; R₁ and R₂ are each independently H, COR₂₀, CO₂R₂₁ or anoptionally substituted C₁-C₄alkyl group; R₃ is H, OR₁₂ or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl oraryl(C₁-C₆)alkyl group each optionally substituted; R₄ and R₅ are eachindependently H, halogen, NO₂, CN, OR₁₃, NR₁₄R₁₅ or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈cycloalkyl group eachoptionally substituted or when attached to adjacent carbon atoms R₄ andR₅ may be taken together with the atoms to which they are attached toform an optionally substituted 5- to 7-membered ring optionallycontaining one or two heteroatoms selected from O, N or S; R₆, R₇, R₈,R₉, R₁₀, R₁₁ and R₁₉ are each independently H, halogen, NO₂, CN, OR₁₆,NR₁₇R₁₈ or a C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl orC₃-C₈cycloalkyl group each optionally substituted; n is 0 or 1;

is a single bond when n is 0 or a double bond when n is 1; R₁₂, R₁₃,R₁₆, R₂₀ and R₂₁ are each independently H or a C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl or arylgroup each optionally substituted; and R₁₄, R₁₅, R₁₇ and R₁₈ are eachindependently H or C₁-C₄alkyl which process comprises reacting acompound of formula II

wherein Hal is Cl or Br and W, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are asdescribed for formula I hereinabove with a compound of formula III

wherein Q is B(OH)₂, Sn(nBu)₃ or Sn(CH₃)₃ and X, Y, Z, R₈, R₉ and n areas described for formula I hereinabove in the presence of a palladiumcatalyst optionally in the presence of a solvent.